minimotifs dysfunction is pervasive in neurodegenerative
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Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19
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Featured Article
Minimotifs dysfunction is pervasive in neurodegenerative disorders
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Surbhi Sharmaa,b, Richard J. Younga,b, Jingchun Chena, Xiangning Chena,c, Edwin C. Oha,d,**,Martin R. Schillera,b,d,*
aNevada Institute of Personalized Medicine, Las Vegas, NV, USAbSchool of Life Sciences, Las Vegas, NV, USA
cDepartment of Psychology, Las Vegas, NV, USAdSchool of Medicine, Las Vegas, NV, USA
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Abstract Minimotifs are modular contiguous peptide sequences in proteins that are important for posttrans-Conflict of interest
terests.
*Corresponding au
**Corresponding
E-mail address: e
edu (M.R.S.)
https://doi.org/10.1016
2352-8737/� 2018 T
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lational modifications, binding to other molecules, and trafficking to specific subcellular compart-ments. Some molecular functions of proteins in cellular pathways can be predicted fromminimotif consensus sequences identified through experimentation. While a role for minimotifs inregulating signal transduction and gene regulation during disease pathogenesis (such as infectiousdiseases and cancer) is established, the therapeutic use of minimotif mimetic drugs is limited. Inthis review, we discuss a general theme identifying a pervasive role of minimotifs in the pathome-chanism of neurodegenerative diseases. Beyond their longstanding history in the genetics of familialneurodegeneration, minimotifs are also major players in neurotoxic protein aggregation, aberrantprotein trafficking, and epigenetic regulation. Generalizing the importance of minimotifs in neurode-generative diseases offers a new perspective for the future study of neurodegenerative mechanismsand the investigation of new therapeutics.� 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is anopen access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Keywords: Minimotif; Posttranslational modification; Trafficking; Binding; Aggregate; Epigenetics; Genetics; Histone code;91
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1. Introduction
Minimotifs, also called short linear motifs, are shortcontiguous peptide sequences or sequence patterns thatencode molecular functions. These functions range fromthe binding of a protein to other proteins and molecules,posttranslational modification (PTM) of a protein, or traf-ficking of a protein to a subcellular compartment. Twomain minimotif databases, Minimotif Miner and the Eukary-otic LinearMotif resource, now house more than one millionminimotif instances [1–6]. Recent proteome-wide analysis
: The authors declare that they have no competing in-
thor. Tel.: 702-895-5546; Fax: 702-895-5728.
author. Tel.: 702-895-0509; Fax: ---.
[email protected] (E.C.O.), martin.schiller@unlv.
/j.trci.2018.06.005
he Authors. Published by Elsevier Inc. on behalf of the Alzhe
commons.org/licenses/by-nc-nd/4.0/).
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of minimotifs with 1000 genomes data determined that thevast majority of minimotifs are fixed in humans, suggestingtheir importance in cellular function [7,8]. At thefundamental level, each minimotif is defined as a sequenceor sequence pattern in a source protein and an activity thatconnects the motif to a target protein. The target proteincan be an enzyme for PTM, an interaction with anothermolecule such as a protein, or a trafficking receptor.
The conservation of most minimotifs and their role inevolution suggests that they might render a significantvulnerability to diseases [5,7–9]. In the first comprehensivereview of minimotifs in human diseases in 2007, our groupnoticed that minimotifs were involved in disease,particularly infectious diseases, and others have expandedon this observation [5,9,10]. There are at least 35minimotifs mutated in more than 20 diseases, includingboth rare and common disorders [11]. These include the three
imer’s Association. This is an open access article under the CC BY-NC-ND
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general classes; binding, PTMs, and trafficking minimotifs.Several annotations for diseases are listed and described onthe Eukaryotic Linear Motif resources website. Approxi-mately 0.1% of missense mutations in the COSMIC somaticcancer mutation database overlap with a minimotif. There are100s of minimotifs encoded by viruses that are used to hijackhost cell processes, several essential for the viral life cycle.
Another line of evidence for the importance of minimotifsin disease is the emergence of Food and Drug Administration(FDA)-approved minimotif mimetic drug therapeutics [11].For example, protein kinase inhibitor drugs such as Gleevec(imatinib mesylate), Iressa (gefitinib), Sprycel (dasatinib),and Stutnet (sunitinib) among others block phosphorylationof minimotifs and have become useful for cancer treatmentand immunosuppression [12]. Drugs that block different pro-teases that cleave minimotifs such as Lotensin (benazepril),Novastan (argatroban), Januvia (sitagliptin), and many HIVprotease inhibitors are also minimotif-directed therapeutics.Peptide hormones tend to have core clusters of amino acidsthat bind to receptors. For example, peptide therapeutics orchemical agonists such as Supprelin LA (histrelin) for theGonadotropin Releasing Hormone receptor, Byetta (exena-tide) for the glucagon-like peptide 1 receptor, SomatulineDepot (lanreotide) for the somatostatin receptors, and opiatessuch as Demerol (meperidine) for opioid receptors mimic thedeterminants of this core cluster in interaction with receptors.There are also antiviral drugs to several lipidation enzymesthat modify minimotifs, and tirofiban is a drug that mimicsthe Arg-Gly-Asp ligand for integrins.
In this review, by exploring the specific role of minimotifsin NDs, we consolidate significant evidence that supports ourhypothesis that minimotifs have distinct and generalizablefunctional roles in ND etiology. Minimotifs are the key con-nections in the cellular molecular network, so it is not surpris-ing that they are vulnerable to pathological dysfunction andthat all NDs have multiple dysfunctions of minimotifs. Byquestioning whether the modification of minimotifs is causalor a consequence of other precipitating events, we recognizeboth are contributing factors to NDs. From the causal perspec-tive, some of the familial genes in NDs have mutations thatdisrupt minimotifs or minimotif targets. Minimotifs mayalso be causal through PTM of the histone code and epige-netics. Other, less direct roles of minimotifs in pathogenesisare through protein trafficking, PTMs, neurotoxic protein ag-gregation, and aggregate clearance.
Because there are approximately 100 NDs known [13], inthis review, we have focused on only the major NDs: Alz-heimer’s disease (AD), Parkinson’s disease (PD), Hunting-ton’s disease (HD), amyotrophic lateral sclerosis (ALS),frontotemporal dementia (FTD), and tauopathies, althoughwhere relevant, other NDs are mentioned.
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2. Types of minimotifs in neurodegenerative diseases
All three types of minimotifs: binding, modifying, andtrafficking, have important roles in neurotoxic aggregate
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formation and clearance, epigenetics through the histonecode, protein trafficking, and PTMs of ND-related proteins.Some of the genes with familial inheritance in NDs harbormutation in minimotifs or enzymes that modify minimotifs,as summarized in Tables 1 and 2 and discussed below.
2.1. PTM minimotifs in neurodegenerative diseases
Previous reviews of NDs summarize the important rolesof PTMs, one general category of minimotifs. There aremore than 500 types of covalent modifications, with most,if not all proteins in the human proteome having one ormore modifications [14]. These PTMs perturb local andglobal structural changes thereby altering protein binding,trafficking, half-lives, activities, and signaling. Therefore,it is not surprising that several of these modifications havesubstantial roles in the pathology of NDs.
2.1.1. Glycosylation/glycationHalf of all proteins inmost cell types undergoglycosylation
and areN-glycosylated at theminimal consensus sequenceNx[S/T] and/or O-glycosylated on Ser or Thr with no specificsequence determinants [15–17]. Protein glycosylationstabilizes protein structural folds and facilitates proteintrafficking, protein quality control, receptor activation, andendocytosis [17,18]. Human mutations in N-glycosylationsites can result in severe disease pathology; for example, afamilial T183A mutation in a NxT glycosylation minimotifin a prion protein (PrP) can result in Creutzfeldt-Jakob disease(CJD) [11,19–22].
Curiously, there are also several germline mutationsimmediately juxtaposed to a N-glycosylation consensussequence: a P504L mutation in WFS1 of Wolframs syn-drome, E196K, V180I in PRP for CJD (P04156), andE196K also in Gerstmann-Straussler disease [23–25].However, whether these mutations alter glycosylation andinfluence pathogenesis is not yet clear.
Also unclear is the observation of altered glycosylation inNDs, a likely downstream event or epiphenomena. On aglobal scale, proteomic analyses of AD brains identified131 GlcNacylation sites in 81 proteins that revealed alteredglycosylation. Another global study on the brain and seraisolated from the HD transgenic mice identified differencesin the amount and the pattern of glycans in mice showing pa-thology [26]. Aberrant glycosylation of an additional tenglycosylated proteins in NDs (AD, PD, and HD) was sum-marized previously [27]. Acetylcholinesterase is abnormallyglycosylated in both CJD and AD [27,28]. Nonenzymaticglycation and aberrant glycosylation of tau are prevalent inAD and FTD [29–32].
2.1.2. PhosphorylationProtein phosphorylation of Ser Q, Thr, or Tyr residues is
biologically significant throughout development of disease.During the pathogenesis of NDs, aberrant phosphorylationresults in the misfolding and aggregation of neurotoxic
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Table 1
Neurodegenerative disorder minimotif summary
NDs
Minimotifs
Aggregate/gene Familial genes Activities References
Alzheimer’s
disease (AD)
b-amyloid plaques,
neurofibrillary
tangles/APP,
MAPT
APP, PSEN1,
PSEN2, MAPT
Proteolysis
Sumoylation
Glycosylation
Lipidation
Acetylation
Methylation
Oxidative PTM
Ubiquitylation
Citrullination
Trafficking
Binding
[24,30,89,98,108,
153,156,164,
168,175,178,
269–273]
Amyotrophic
lateral sclerosis
(ALS)
Hyaline
inclusions/SOD1
SOD1 Ubiquitylation
Sumoylation
Phosphorylation
Lipidation
Oxidation
S-nitrosylation
S-glutathionylation
Trafficking
[82,85–87,
108,274–277]
Batten (neuronal
ceroid
lipofuscinosis)
Aggregation/CSPa Lipidation [63]
Creutzfeldt-Jakob Prion plaques/(PrP) PRNP Glycosylation
Trafficking
Phosphorylation
Acetylation
Methylation
Ubiquitylation
Citrullination
Binding
[10,23,99,
175,262,
278–281]
Frontotemporal
dementia/
degeneration (FTD)
Neurofibrillary
tangles/tau
tau Phosphorylation
Sumoylation
Ubiquitylation
Glycosylation
[27,32,
33,74,120]
Huntington’s
disease (HD)
Neuronal
inclusions/HTT
HTT Sumoylation
Glycosylation
Ubiquitylation
Proteolysis
Trafficking
[52,101,
108,273,282]
Parkinson’s
Disease (PD)
Lewy bodies/SNCA SNCA
LRRK2
GBA
VPS35
EIF4G
DNAJC13
PRKN
Proteolysis
Sumoylation
Glycosylation
Lipidation
Acetylation
Methylation
Oxidative PTM
Ubiquitylation
Phosphorylation
Citrullination,
Trafficking
[34,88,96,
108,270,
272,273,
283–290]
Spinal and
bulbar
muscular
atrophy
(SBMA)
Aggregation/AR Sumoylation
Ubiquitylation
Phosphorylation
of non-aggregating tau
[108,291–294]
Spinocerebellar
ataxia (SA)
Neuronal
inclusions/SCA
SCA Sumoylation
Phosphorylation
Ubiquitylation
Trafficking
Proteolysis
[48,100,101,
108,174,
295,296]
(Continued )
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Table 1
Neurodegenerative disorder minimotif summary (Continued )
NDs
Minimotifs
Aggregate/gene Familial genes Activities References
Tauopathies Neurofibrillary
tangles/tau
MAPT Phosphorylation
Glycosylation
Acetylation
Methylation
Ubiquitylation
SUMOylation
[113,297]
Abbreviations: PTM, posttranslational modification; CSPa, cysteine-string protein a.
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proteins. For example, abnormally hyperphosphorylated tauhas been associated with aggregates in AD and other tauopa-thies [33]. In addition, more than 40 sites of phosphorylationin tau have been described that enhance or reduce its aggre-gation propensity [33,34]. S129 is the most prominent tauphosphorylation site. The degree of tau phosphorylationdiffers in AD and FTD, which increases its propensity toaggregate and/or induce toxicity [35,36].
Although the causation and correlation between the phos-phorylation and a–synuclein (aSyn) aggregation and toxicityin Lewy bodies remain unclear, the phosphorylation state ofaSyn in Lewy bodies is well established [37,38].Approximately 90% of the phosphorylated aSyn is present inLewy bodies, a hallmark of PD, and other synucleinopathies[37,39–44]. Of the 17 potential phosphorylation sites inaSyn, S87 is the most tightly associated one withsynucleinopathies [45]. Several potential reasons for the lackof consensus among different studies may be due to in vitroand in vivo comparisons, different efficiencies of kinases, andthe balance between the phosphorylation and dephosphoryla-tion of proteins in different model systems.
Both Parkin and PTEN-induced putative kinase 1(PINK1) are mutated in PD with approximately half of theearly onset familial cases caused by Parkin [46]. Autoinhibi-tion of Parkin, an E3 ubiquitin ligase, is released on its phos-phorylation at S65 by PINK1 [47,48]. Activated Parkin
Table 2
Minimotif enzymes, activities, and substrates in familial NDs
ND(s)
Minimotifs
Enzymes
AD PS1, PS2
ALS/FTD
FTD
FTD
FTD TBK1
FTD VCP, CHMP2B, TARDBP, SQSTM1, DCTN1
HD -
PD Parkin
PD LRKK2, PINK1
PD UCH-L1
SMA UBE1, DYNC1H1
Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; F
disease; SMA, ---.
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initiates a downstream ubiquitylation pathway thatregulates the quality control of proteins in PD [49].
Phosphorylation is also important for several genes with afamilial linkage to NDs. At least part of leucine-rich repeatkinase 2’s (LRKK2) pathogenicity in PD is due to its kinaseactivity and its substrate recognition likely by minimotifsthat bind its WD40 domain [50]. Ataxin1 has polyglutamine(polyQ) tracts important for the pathogenesis of spinocere-bellar ataxia (SA). Phosphorylation of S776 in Ataxin1 atan Akt phosphorylation minimotif increases cytotoxicity oflonger polyQ tracts [51,52]. Phosphorylation likely has aprotective role in ALS as a T2D phosphomimetic mutationstabilizes superoxide dismutase (SOD) in the presence ofother destabilizing pathogenic mutations [53]. Haplotypeswith this variant and a destabilizing SOD variant is onepossible explanation for variable penetrance of the patho-genic mutations.
2.1.3. LipidationFatty acid attachment to proteins anchors them to mem-
branes [54]. Some common lipidation PTMs are palmitoyla-tion, N-myristoylation, farnesylation, geranylgeranylation,GPI addition, S-diacylglycerol addition, and prenylation[54]. We do not know of a direct linkage of lipidation withproteins harboring mutations in NDs, suggesting that lipida-tion is a downstream change. However, several proteins with
Activity Substrates
Proteolysis APP
SOD1
Phosphorylation Tau
Binding SQSTM1
Kinase
HTT
Ubiquitylation a-SP22
Phosphorylation
Proteolysis Ub
Ubiquitylation
TD, frontotemporal dementia; HD, Huntington’s disease; PD, Parkinson’sQ24
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established roles in ND pathogenesis are covalently linked tofatty acids supporting some role. Palmitoyl acyltransferases(PATs), enzymes that catalyze protein palmitoylation recog-nize theJbxxQP minimotif (J, an aliphatic amino acid; b,a C-b branched amino acid Val, Ile, or Thr) in Huntingtin(HTT) [55–61]. ZDHHC17 is a PAT specific for neuronalproteins, including HTT. The reduced palmitoylated HTTin HD implies a reduced activity of PAT for HTT.Palmitoylated HTT has shorter polyQ tracts supporting aprotective role against HT. Similar to palmitoylation,myristoylation of HTT is also reduced in HD [62]. Onepossible explanation is that the expansion of the polyQ tractinterferes with this PTM. Palmitoylation of mutant superox-ide dismutase 1 (SOD1) and mutant cysteine-string protein amay play a role in the etiology of familial ALS and neuronalceroid lipofuscinosis, respectively [63–66].
In AD, a palmitoylated amyloid precursor protein (APP)is restricted to the Golgi, enhancing proteolytic processingthat favors amyloidogenesis. Several other substrates ofPATs associated with AD, PD, and HD are discussed [61].
Other examples of lipidation impacting NDs are a glyco-sphingolipids binding minimotif [K/H/R]x(1-4)[Y/F]x(4-5)[K/H/R], with at least one Gly at x(1-4) is present in aSyn, b-amy-loid peptide, and PrP [67,68]. Of the many gangliosides (GM),aSyn specifically binds GM1 and GM3 inhibiting fibrilformation in PD. Conversely, b-amyloid binding to GM1initiates fibril formation in AD [69,70]. PrP localization tolipid rafts stabilizes its nonpathogenic state. [L/V]x(1–5)Yx(1–5)[K/R] is a cholesterol recognition/interaction minimotifidentified in aSyn as VLYVGSK, on binding cholesterol wasaSyn aggregates in neurons [68,71]. Other types of fatty acidattachment are prenylation, geranylgeranylation, andfarnesylation. A recent review summarizes accumulatingevidence supporting a role for prenylation of small GTPasesin Ab production and secretion in AD [72].
2.1.4. Acetylation and methylationThe role of protein acetylation and methylation in NDs
was previously reviewed [73]. These PTMs are commonfor histones and can impact epigenetic inheritance, a topicaddressed later in the epigenetics section. Protein acetylationand methylation increase the surface area of, and depolarizesLys and Arg residues, a modification that generally drivesnew protein-protein interactions.
Protein acetylation is a reversible attachment of acetylgroup to the a-amino group of either the N-terminus or theε-aminogroup of theLys residues [74].Acetylation ofLys res-idues in tau inhibits its degradation and induces its aggregationin AD [75,76]. In particular, the K174Qmutant tau mimics anacetylated Lys state, leading to more severe neuronal atrophyin mice. Conversely, acetylation of a-tubulin, a PTM thatincreases its stability, is decreased in AD [73]. FTD micemodels have similar effects of acetylated tau and the K174Qmutant [32,77]. aSyn, HTT, b-amyloid, and PrP are allsubject to acetylation with either a protective or adetrimental effect on ND pathology [74,78–82].
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The ε-amino moiety of Lys can be mono-, di-, or tri-methylated, and Arg can be mono- or di-methylated.Methylated residues identified in tau are located in themicrotubule binding repeat region, thus, may block its in-teractions with microtubules [75]. Tandem mass spectrom-etry analysis of a human AD brain identified seven Lysresidues (K44, K163, K174, K180, K254, K267, and K290) intau that are monomethylated, and neurofibrillary tanglesare immunopositive [75]. In vitro experiments demonstratethat Qmethylation reduces deimination of Arg residues inMBP, a modification that may sensitize T-cells for autoim-mune attack of myelin in multiple sclerosis (MS) [83].
2.1.5. Nitrosylation, glutathionylation, and other oxidativePTMs
There are several types of Cys REDOX PTMs and corre-sponding minimotifs in NDs [84]. During oxidative stress,two Cys residues can oxidize creating intermolecular disul-fide bridges and protein aggregation. Some Cys thiol groupsin SOD1 are oxidized to sulfenic, sulfinic, and sulfonicacids, decreasing the stability of the protein and renderingit prone to aggregation in ALS patients [63,85–88].Similarly, S-glutathionylation of Cys residues in SOD1induces its aggregation in ALS [89,90].
Aberrant protein S-nitrosylation in several NDs,including ALS, AD, and PD, has been previously reviewed[88,91]. A global analysis of mouse brain identified 31nitro-tyrosine PTMs, more than half of which have beenimplicated in PD, AD, and other NDs [92–94]. Theconsensus motif for nitric oxide reaction with proteins is[K/R/H/D/E]C[D/E], where the Cys residues is covalentlyattached to nitric oxide [95,96]. Protein S-nitrosylation caninduce protein misfolding and aggregation [95,97].Aberrant S-nitrosylation of many proteins (parkin, PDI,DNM1L, CDK5, PRRX2, GAPDH, PTEN, AKT1, MAPK,IKBKP, and XIAP) may contribute to neurodegenerationthrough multiple pathways [91]. For example, aberrant S-ni-trosylation of PDI decreases its enzymatic activity, therebyinhibiting its neuroprotective functions [91].
2.1.6. UbiquitylationMany misfolded and damaged Qproteins are targeted for
ATP-dependent proteolysis by conjugation with ubiquitin,an 8.5 kDa protein. The role of ubiquitylation in NDs waspreviously summarized [98]. Proteins that aggregate inNDs tend to be ubiquitylated, likely for initiating targetedprotein degradation. In the cerebral cortex Qof patients withAD, the cerebral spinal fluid of patients with CJD, andaSyn in patients with PD, ubiquitylation of neurofibrillarytangles is increased [99–102]. Tau, the protein thatoligomerizes in these tangles, is ubiquitylated at K254 inAD, and the ubiquitylated tau may be blocked by Lysacetylation in FTD [32,76]. A PolyQ tract in Ataxin-1 in-duces its aggregation in the nucleus and leads to ubiquity-lated SA type 1 (SCA-1), inducing cytotoxicity in SA[103]. Ubiquitylated polyQ tracts in HD and other triplet
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repeat NDs enhance intranuclear protein aggregation in neu-rons [104–106]. Additional PTMs in the polyQ tracts in 12proteins involved in the pathology of 9 NDs are known[107]. SCF E3 ubiquitin ligase binds survival motor neuronprotein through a phosphodegron signal, DSGxx[S/T],where the Ser is phosphorylated [108]. This suggests thatoligomerization of the mutant survival motor neuron poten-tially sequesters the degradation signal and stabilizes sur-vival motor neuron, a potential pathogenic pathway inspinal muscular atrophy [108,109].
2.1.7. SumoylationSmall Ubiquitin-like Modifiers (SUMOs) are ubiquitin-
like proteins covalently attached to other proteins atJKXE/D minimotifs. There are four SUMO genes in hu-mans [110]. SUMO normally functions in protein stability,nuclear-cytosolic transport, and transcriptional regulation.Many key proteins in ND pathogenesis are sumoylated andimplicated in disease mechanisms [111–113]. In AD,sumoylation of APP decreases Ab production, andsumoylation stabilizes tau by inhibiting itsphosphorylation and ubiquitylation [113–116]. Similarly,in PD, sumoylation of aSyn inhibits its aggregation[117,118]. The pathogenic fragment of HTT is sumoylatedin HD, and SOD aggregation in ALS is also effected [119–122]. Pathogenic mutation of sumoylated residues invalosin-containing protein/p97 inhibits its translocation tothe nucleus, the formation of stress granules, reduction ofhexamer formation, and eventually, inhibition of its clear-ance. These mutants are prevalent in FTDs [123].
2.1.8. CitrullinationCitrullination is an irreversible PTM type of minimotif
[124]. Peptidylarginine deiminases deiminate Arg residuesin proteins converting this amino acid to citrulline. Becausearthritic patients have anti-citrullinated protein antibodies,citrullination may be related to some of the neuroinflamma-tory aspects of NDs. Abnormal protein citrullination isknown for AD, PD, including Lewy bodies, and in prion dis-eases [125–127]. Autoimmune attack of citrullinatedproteins may be prevalent in ND neuroinflammation[128,129]. Although MS is not considered a ND,citrullination of the major myelin component, MBP mayplay a role in the autoimmune attack of myelin in MS[130]. Deimination depolarizes MBP and is a modificationthat may trigger the demyelination of axons in MS [131].
2.1.9. EndoproteolysisProteolysis is central to the degradation of misfolded pro-
teins by the ubiquitin-proteasome system and autophagy,both driven through minimotifs and central to NDs [132].The inherent role of endoproteolysis in neurodegenerationwas founded in the familial genetics of APP processing tob-amyloid and was recently reviewed [133]. In early onsetAD, b-secretase and g-secretase cleave APP-producingamyloidogenic Ab40 or Ab42 [27,134,135]. Familial
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mutations in the protease processing minimotif sites inAPP cause overproduction of amyloidogenic peptidefragments.
Other NDs have proteolysis minimotifs as well. In pa-tients with PD, familial mutations were identified inUCHL1, a protease that cleaves ubiquitin and colocalizeswith Lewy bodies. Cleavage of the furin prohormone con-vertase cleavage Qsite (KGIQKREA) in putative type-II sin-gle-spanning transmembrane precursor protein (BRI)yields a small C-terminal amyloidogenic peptide fragment[136]. These fragments are present in the amyloid fibrils ofpatients with Familial British dementia [137–139]. Severalproteases cleave HTT at minimotifs producing peptideaggregation and neurotoxic peptides [140–144].
2.2. Trafficking and autophagy minimotifs inneurodegenerative diseases
Minimotifs are important in protein trafficking to andfrom organelles and are relevant to several NDs[1,145,146]. Defects in endocytic and synaptic vesicletrafficking, Golgi trafficking, retrograde transport, andlysosomal autophagy are apparent in PD and AD[145,147,148]. Trafficking minimotifs are essential formost protein trafficking events, have been previouslyreviewed, and a few typical examples are presented [148–151]. LRKK2 is a kinase/GTPase with mutations inpatients with familial PD [152]. LRRK2 has a WD40 inter-action domain that binds to synaptic vesicles and severalLRRK2 interactors function in vesicular trafficking[50,153]. Through phosphorylation of S75 in endophilin,LRKK2 plays a role in synaptic vesicle endocytosis inDrosophila [154]. LRKK2 is also involved in retrogradetrafficking through a functional association with VPS35,another protein mutated in familial PD.
The role of trafficking of APP in AD pathogenesis hasrecently been reviewed [135]. A KFERQ minimotif at theend of APP binds SCG10 and is essential for traffickingAPP to lysosomes for degradation [155,156]. The KDELreceptor binds ER resident proteins containing the KDELminimotif and returns them to the endoplasmic reticulum[157]. The receptor is redistributed to lysosomes and stimu-lates autophagy, when aberrant SOD in ALS, aSyn in PD,and HTT in HD are expressed [158].
The cytoplasmic domain of APP contains a YxNPxYsequence, an internalization minimotif that traffics APP toendosomes [159,160]. The same minimotif in APP bindsto adaptor proteins, including LDL-Rs, FE65, X11,SNX17, and Dab2, which regulate APP trafficking andthereby regulates b-amyloid production [159].
Mutant ataxin-1 has a nuclear localization signal, whichis required to mediate toxicity of variants with long polyQtracts in SAs [51,161]. Mutations in the VxPx. minimotifin rhodopsin cause autosomal dominant retinitispigmentosa, a progressive ND of photoreceptor neurons[162]. This C-terminal minimotif is essential for trafficking
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of rhodopsin from the trans-Golgi-network [163]. This mini-motif also binds to ADP-ribosylation factor 4, a rhodopsintransport carrier, regulating the otherwise bulk flow of pro-teins to photoreceptor rod outer segments.
Chaperone-mediated autophagy, in addition to ubiquityla-tion, is another mechanism that maintains protein quality con-trol in NDs [164]. The substrates of autophagy contain aKFERQ-like minimotif that is exposed potentially only aftera PTM-induced conformational change. These minimotifsinteractwith the chaperone complex and are translocated to ly-sosomes via lysosomal-associatedmembrane protein 2A, a re-ceptor that triggers autophagy. AVKKDQ minimotif in aSyntargets it for autophagy [165,166]. aSyn A30P and A53Tmutants may cause familial PD by interacting withlysosomal-associated membrane protein 2A. These mutantproteins fail to translocate into the lysosomal lumen, effi-ciently stalling the process of autophagy.
Autophagy may be a step in the pathology of PD and HD.Autophagy-targeting minimotifs (QVEVK, KDRVQ) in tauare important in a neuronal cell model of tauopathies [167].On binding the chaperone complex, Cathepsin L, a lysosomalcysteine protease cleaves mutant tau proteins producing pep-tide fragments that aggregate [167]. Amore detailed overviewof autophagy enumerates eight proteins containing 17confirmed and putative autophagy-targeting minimotifs inproteins involved in PD etiology [168]. Mutant KDRVN andNEIKV minimotifs in HTT are recognized by the autophagymachinery, but an extended C-terminal polyQ track in HTTdelays targeting to the lysosomes. This may result in severeHTT aggregation in the neurons of patients with HD [169].
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2.3. Binding minimotifs in neurodegenerative diseases
One of the most important activities of minimotifs is forproteins to bind other molecules, which is central to manycellular pathways and processes. Interestingly, many typesof bindingmotifs propagate neuronal atrophy inNDs. A link-age analysis of a Turkish kindred identified an autosomalrecessive variant encoding a D458Vmutation in the C-termi-nal PDZ binding motif of SANS protein in patients with theatypical Usher syndrome [170,171]. Through SH3 bindingminimotif, RTPPKSP, tau binds the SH3 domains of Fynand Src nonreceptor tyrosine kinases, which alsophosphorylate tau [172,173]. Because hyperphosphorylatedtau is a hallmark of AD [174]. MED25 binds SH3 domainsof Abelson family protein kinases. The A335V mutation inthe proline-rich SH3 binding motif of MED25 decreasesbinding specificity imparting interactions with a broaderrange of nonphysiological proteins with SH3 domains. Thismutation causes Charcot-Marie-Tooth disease 2B2 [175]. AYENPTY minimotif in APP interacts with PTB domains ofMint proteins trafficking and processing APP [176–178].Ataxin has a RxxSxP 14-3-3 binding minimotif thatenhances the toxicity of its polyQ tracts in SA [179].
The GxxxGxxxG, glycine zipper minimotif binds choles-terol and has an established role in oligomerization of pro-
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teins, including Ab and PrP [180–182]. Cholesterolbinding to APP may contribute to amyloidogenesis andAD [180]. In the postsynaptic terminal, b-amyloid recruitsPTEN, a lipid phosphatase in a PDZ domain-dependentmanner inducing a malfunctional state of amyloids [183].A PTEN mutant lacking its PDZ domain protects againstamyloid toxicity.
2.4. Minimotif cooperativity
Minimotif cooperativity is perhaps one of the most under-studied aspects of minimotif function and is likely an impor-tant factor for understanding molecular dysregulation inNDs. Many proteins, including those associated with NDs,have more than five minimotifs, and there are now numerousexamples of how one minimotif can induce or create a newminimotif, or compete with other minimotif targets for thesame site. These often impact a protein activity or cell pro-cess. Several examples of minimotif cooperativity arementioned in the other sections, and a few are highlightedhere. In PTM minimotifs, certain residues either competefor a particular PTM or induce further modifications. Forexample, phosphorylation often precedes modificationssuch as sumoylation and ubiquitylation [38]. In patientswith AD, tau phosphorylation follows an initial glycosyla-tion modification [30,184]. When MARK2 phosphorylatestau, it is no longer recognized by E3 ligase, preventing itsdegradation [185]. Methylation minimotifs in tau are posi-tioned to engage in cross talk with phosphorylation [75].
3. Minimotifs in aggregates
Protein aggregation is common in the etiology of mostNDs [186]. b-Amyloid and tau are the major constituentsof neuritic plaques and neurofibrillary tangles, respectively.Lewy bodies are intracellular aggregates of aSyn in PD andother synucleinopathies. Proteins with extended polyQ re-peats aggregate into nuclear and cytosolic inclusions inHD, SA, and dentatorubral-pallidoluysian atrophy. A hall-mark of ALS is cytoplasmic inclusions of SOD1.
Although abnormal protein aggregation in neurodegener-ation is well established, the generalized role of minimotifsin aggregation was not previously emphasized. There areseveral genes with familial inheritance in NDs that encodeminimotif target enzymes or their substrates. These genes,minimotifs, and their activities are listed in Table 2. b-Am-yloid, the central component of plaques, is ubiquitylatedand phosphorylated, which regulates the stability of plaques[187–189]. Most tauopathies have the common molecularabnormality of hyperphosphorylation of tau, whichaggregates into neurotoxic inclusions [190]. Furthermore,there are at least a dozen other PTMs that modulate tau ag-gregation [116,191]. Lewy bodies are ubiquitylated,sumoylated, phosphorylated, nitrosylated, and also have aunique PTM created by a dopamine radical adduct[117,192,193].
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At least 48 PTMs of protein have been identified in NDs,and other neurotoxic proteins with long polyQ tracts havemany PTMs [194,195]. Because minimotifs are located onthe surfaces of all proteins and cover almost the entiresurface of many proteins [196–199], it is not surprisingthat perturbing minimotifs results in abnormal neurotoxicaggregation. Given their prevalence in neurotoxicaggregate formation and stability, a betting understandingof how minimotifs cooperate to induce and inhibitneurotoxic aggregates would provide a betterunderstanding of ND etiology and open the door for newtypes of therapeutic intervention. As such, minimotifmimetics should be considered as targets for reducingaggregation in NDs.
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4. Genetics and epigenetics of minimotifs in NDs
Over the past decade, genome-wide association studies(GWASs) have advanced our understanding of the geneticbasis of human disease [200]. Similar to other disorders,NDs have a familial component with rare variants of largeeffect and a more prevalent sporadic component withmany common variants of small effect. Given that minimo-tifs are located at the interface between proteins and areimportant constituents of cellular networks, it is no surprisethat several of these motifs have been highlighted in GWASsand in the biology of key cell types such as neurons, astro-cytes, and microglia. Some of the earliest advances in ge-netics were derived from genetic linkage and positionalcloning in NDs and have led to newer studies relying ongenome-wide quantitative trait analyses such as biomarkersor endophenotypes [201].
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4.1. Genetics
Through the combination of high-throughput genotypingplatforms and next-generation sequencing technologies,disease-causing genetic variants and genetic factors necessaryfor protection against disease have been discovered at an un-precedented rate. While such technologies have transformedmonogenic disease research, several challenges continue tohamper the discovery of actionable genomic variants in com-plex disorders. For example, variants of unknown significanceand an abundance of neutral variants or variants with modesteffect size continue to be produced at a staggering rate. Assuch, leveraging next-generation sequencing for discoveryhas been contingent on carefully constructed studies of largesample sizes and judicious selection of participants with accu-rate and detailed phenotyping. Here, we focus on AD and PDas exemplars of NDs, and we also discuss a pervasive role ofgenetic variants in minimotifs.
4.1.1. Alzheimer’s diseaseAD is a common neurodegenerative disease and a leading
cause of dementia with progressive loss of memory,problem-solving skills, and communication. Due to recent
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improvements in life expectancy, AD is predicted to affect1 in 85 people globally by 2050 [202]. As a heterogeneousdisease, AD is caused by a combination of environmentaland genetic factors and current estimates of AD heritabilitylie between 60-80% [203]. Late-onset AD accounts for morethan 95% of all AD cases and is caused by a complex under-lying genetic architecture. To date, over 40 GWASs andmeta-analyses have identified a few hundred genes and sin-gle nucleotide polymorphisms; these include variants inapolipoprotein E (APOE) among other notable gene candi-dates [204]. In contrast to late-onset AD, early onset AD iscaused by highly penetrant variants located primarily inthree genes, APP (located at 21q21.2), presenilin 1(PSEN1, located at 14q24.3), and presenilin 2 (PSEN2,located at 1q42.13) [202]. Structural variants are associatedwith complex neurological traits; for example, duplicationof APP causes early-onset AD with cerebral amyloid angi-opathy [205,206]. To empower current association studies,new attempts at incorporating quantitative endophenotypessuch as age at onset analysis and expression quantitativetrait loci are being conducted [207].
Minimotif activities are prevalent in genes associatedwith AD. On examining disease genes with penetrant vari-ants, we identified at least 11 activities that could be associ-ated with disease: proteolysis, sumoylation, glycosylation,lipidation, acetylation, methylation, oxidative PTM, ubiqui-tylation, citrullination, trafficking, and binding (Tables 1 and2). Intriguingly, more than half of all APP mutations arelocated at the secretase proteolytic cleavage sites or thetransmembrane domain, a region on exon 16/17 (www.molgen.ua.ac.be/ADMutations). In addition, loss-of-function AD Qanimal and cellular models suggest that suchminimotif activities are indeed perturbed functionally. Assuch, we predict that coding and structural variants thatimpact minimotif function will be key nodes in ND [208].
4.1.2. Parkinson’s diseaseAs the second most common neurodegenerative disorder
after AD, PD results from the loss of dopaminergic neuronsin the midbrain and the accumulation and aggregation ofaSyn in Lewy bodies [209,210]. While rare before the ageof 60 years, up to 4% of the population at the age of80 years has PD [211]. Similar to AD, the genetic architec-ture of PD is complex, and only 5-10% of all patients sufferfrom an apparent monogenic form of PD [211]. These rareand penetrant variants are located within 19 disease-causing genes such as aSyn (SNCA, located at 4q22.1),LRRK2 (located at 12q12), and acid b-glucosidase (GBA,located at 1q22) and segregate with the disease in an auto-somal dominant or recessive pattern [212]. GWASs haverecently identified more than 40 risk loci, including candi-date genes that LRRK2 phosphorylates [213].
In a similar minimotif analysis of PD, we note that 11 activ-ities are potentially impacted. These include the following: pro-teolysis, sumoylation, glycosylation, lipidation, acetylation,methylation, oxidative PTM, ubiquitylation, phosphorylation,
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citrullination, and trafficking (Tables 1 and 2). To verify therelevance of these predictions, we examined how familial mu-tations inLRRK2might affectminimotif activities (Table 2).Onfocusing on phosphorylation, we noted that disease-associatedmutations, Y1699C and I2020T (nonphosphorylated residues),disrupted the phosphorylation of constitutively phosphorylatedresidues at the amino terminal, resulting in attenuated LRRK2function [214]. These findings, and additional LOF and GOFmodels, suggest that detailed analyses of minimotif functioncan identify feedback control mechanisms and novel networksthat drive PD biological processes [215].
4.1.3. Microglia and NDsMicroglia are the highly specialized macrophages of the
central nervous system, accounting for 10–15% of all cells inthe adult brain [216]. Significant advances have been madein understanding the roles of microglia in the developmentof the brain, such as in neurogenesis, synaptic pruning, sur-veillance, and homeostasis [217]. In contrast, defining therole of microglia in central nervous system disorders hasproven to be more difficult. Given that microglial activationand neuroinflammatory processes play a critical role in thepathogenesis of NDs, biological components linked to mi-croglial biology have been associated with AD etiologythrough GWAS; these include the following: TREM2 (trig-gering receptor expressed on myeloid cells 2), CD33, CR1(complement receptor 1), ABCA7 (ATP-binding cassette,sub-family A, member 7), SHIP1 (also known as INPP5D,inositol polyphosphate-5-phosphatase D), APOE, CLU(clusterin), CD2AP (CD2-associated protein), and EPHA1(EPH receptor A1) [218–222].
Complementing the human genetic studies, knockoutmice models of genes from GWAS have allowed forcause-effect in vivo investigations into disease pathogenesis.As expected, a fraction of these genes is implicated in theregulation Ab accumulation. For example, ApoE- andCLU-deficient APP transgenic mice exhibit earlier andmore extensive Ab deposition compared with control mice[223]. In addition, CD33 inactivation in App/Psen1 micereduced Ab accumulation and plaque burden, whereasAbca7 deficiency in App/Psen1 and TgCRND8mice acceler-ated Ab generation [224–226]. Importantly, variants ofTREM2, an immunoglobulin-like cell-surface receptor spe-cifically expressed in brain microglia, confer a 2- to 4-foldincreased risk for AD [221]. However, exactly how Trem2variants confer AD risk is still under investigation. Thusfar, the most consistent and striking observation is a strongdecrease in microgliosis surrounding Ab plaques of AD inTrem2 haploinsufficient and Trem2 deficient mice; a similarimpairment in microgliosis has also been reported in mousemodels of prion disease, stroke, and MS, suggesting a crit-ical role for TREM2 in supporting microgliosis in responseto pathology in the central nervous system.
A loss-of-function mutation in the lipid sensing function,a minimotif activity of Trem2 deficient mice may be the un-derlying mechanism for the loss of microglia proliferation
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and microglial response to Ab plaques or reduced infiltrationof peripheral macrophages [227,228]. In addition, Trem2deficiency leads to exacerbated aggregation of tau in amouse model of tauopathy [229]. These findings demon-strate that TREM2 has complex multiple roles in regulatingAb and tau pathologies that may reflect its distinct functionsat different stages in AD pathology [230]. These findingsalso highlight how minimotif activities are present in severalproteins relevant to microglial biology.
Minimotifs are a source of functional genetic variationand are important targets in natural selection and evolution[231]. Given their prevalence in NDs, we must considerthat common NDs may include a cumulative compositionof many minimotif variants that cause network dysfunction.This could provide an explanation for missing heritability inNDs. One exciting possibility is that minimotifs maycontribute to the genetic risk of neurodegeneration; however,this will require additional study.
4.2. Epigenetics
Epigenetics refers to inheritance that is notmediated throughDNA sequence but through covalentmodifications or noncova-lent DNA interactions. A number of recent reviews highlightthe emerging role of epigenetics in normal brain function andneurodegeneration [232,233]. Major mechanisms ofepigenetics are DNA methylation and PTM of histones/nucleosomes, which is often referred to as the histone code[234]. Minimotifs are the foundation of the histone code. En-zymes that covalently modify minimotifs, including those inhistones, are central to AD, PD, ALS, HD, and other polyQtrack disorders summarized in recent reviews [235–240].
The role of minimotifs in ND epigenetics is of general in-terest for ND beyond disease etiology. One emerging area ofinterest is drugging the enzymes that modify protein compo-nents of nucleosomes. Considering the broad role of epige-netics in NDs, there are several drugs such as histonedeacetylase inhibitors that are being tested inpreclinical inves-tigation and are in different phases of clinical trials [233].
Epigenetics may also explain at least part of the ubiqui-tous “missing heritability” for common diseases such asthe major NDs. Testing the role of epigenetics in PD mayprove difficult without considering the effects of minimotifs.This is because our group has previously reported histonecode variability in the population [7]. Approximately 4%of the minimotifs in histone tails had common alleles in hu-mans that were loss-of-function for the PTM. This suggeststhat the histone code may be wired differently among peo-ple, inferring differing epigenetic responses to the environ-ment [7]. This may be critical to account for in any studythat attempts to uncover the epigenetic basis of NDs.
5. Minimotifs as therapeutic targets for NDs
The Therapeutics Peptide Database has no FDA-approved drugs for treating NDs [241]. Despite this lack of
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success, the investigation of minimotif-directed therapeuticshas been and remains of high interest and potential. Thera-peutic interventions based on minimotifs have been dis-cussed in detail for AD, PD, HD, and CJD [242–249].Since APP was one of the first genes connected withfamilial AD and the aggregation of Ab is a predominatefeature of late-onset AD, there has been much interest in in-hibiting Ab production. Inhibitors of a, b, and g-secretasethat inhibit APP processing, Ab production, and aggregationis still under clinical study as was recently reviewed [250].
Several other minimotif-directed therapeutics are beinginvestigated for reducing aggregation of neurotoxic proteins.One central therapeutic approach, although not directed to-ward minimotifs, is to lower levels of the neurotoxic proteinby antisense oligonucleotide therapy [251,252]. Theubiquitin-proteasome system is strongly associated withNDs and is a target for new therapies with compounds thatstimulate proteasome-mediated aggregate degradation ortherapeutics that target specific proteins for proteome degra-dation [98,253]. Aggregation-blocking peptides such asSNWKWWPGIFD, a polyQ-binding peptide against HTT;GAVVT, a aSyn self-aggregation blocking peptide againstPD; and a NPxY. PTB domain-interacting endocyticminimotif-blocking peptide against AD are also being tested[254–256]. Glycosaminoglycans mimetics are decoyinhibitors of covalent glycosaminoglycan attachment toAb, blocking its aggregation [257]. Polyanions such as pen-tosane polysulfate interferewith aggregation of glycosylatedPrP have shown promise in a preclinicalmodel [258]. Severalkinase inhibitors block GSK3b, CDK5, and other tau kinasesto reduce tau phosphorylation, and hence their aggregationsare being investigated for AD and tauopathies [33].
Given the role of neuroinflammation and autophagy inAb removal, drugs that enhance amyloid degradation areof growing interest. Many analogs and approaches to targetautophagy machinery were previously reviewed [132,169].Rapamycin is a FDA-approved drug that inhibits the kinaseactivity of mTOR and improves memory function in modelorganisms. Preclinical studies of mice show that rapamycinreduces Ab and tau-associated pathologies by increasingautophagy [255,256,259]. Although not related tominimotifs, lithium also induces autophagy and clearanceof HTT, synuclein, and PrP [258].
Three histone deacetylase inhibitors were approved bythe FDA for treating various types of cancer [259]. SinceNDs have an epigenetic component (addressed earlier), his-tone deacetylase inhibitors and other drugs targeting epige-netic modifications may be useful for treating NDs. This firsttest of hypothesis is currently under investigation with clin-ical trials on ORY-2001 for treating AD. ORY-2001 inhibitshistone methylation and reduces cognitive impairment andneuroinflammation in rodent model.
Althoughminimotif-targeted drugs are not a major class oftherapeutics, as we learn more about minimotifs, we hypothe-size that their broad influence on disease will likely becomemore evident and become useful for treatment of NDs.
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6. Conclusion
Minimotifs are short peptide sequences that encode a mo-lecular function. Their role in cancer and infectious diseaseshas been previously established [9–11]. In this review, wesummarize the evidence supporting minimotifs as keyregulators of ND pathogenesis and describe numerousexamples of causative cases in familial NDs.
Collectively, numerous studies support centrality of mini-motifs to NDs, much of which was previously reviewed[33,111,119,125,131,192,253,260–264]. Our observationof the generalized minimotif pervasiveness in NDs raisesseveral interesting questions. Particularly, why areminimotifs so prevalent in NDs, and can this observationteach us anything more general about ND etiology?
We consider that answers to these questions may arisefrom the role of minimotifs in protein and larger networks.NDs have an additional layer of complexity when comparedwith other human diseases. Many diseases are founded inphysiological dysfunction of the cellular network that man-ifests as the emergent network properties of symptoms andeven death. This network dysfunction is rooted in dysfunc-tion of the molecular network with cells where minimotifshave an important role. However, networks are more com-plex in NDs because the symptoms arise from emergentproperties of dementia, loss of motor control, and othermental health symptoms. These symptoms are due to break-down of an additional network, the neuronal network.Cognitive states are considered emergent properties of anetwork [265].
Why are minimotifs a point of vulnerability? Thus far,about a million minimotifs have been experimentally veri-fied with large growth anticipated [4]. Minimotifs are thekey determinants that enable proteins work together in anetwork as a basis for emergent properties in the cell suchas neurotransmission and neuroinflammation. Most complexnetworks, including biological networks and the minimotif/protein network, have topologies of cliquish small world net-works and have the property of robustness.
Robustness protects the system against immediate shockthrough adaptive mechanism engineered over time throughselection and evolution. Those mutations that target key vul-nerabilities in the network cause failure and prenatallethality.
While the protein/minimotif, cellular, and neuronal net-works are evolutionarily tuned for robustness, like anynetwork, they can fail, the failures of interest herein beingNDs and death. The study of ND disease etiology hasinformed us of two general categories of disease failure, fa-milial, and sporadic. Familial ND network failure may arisefrom hub protein dysfunction [266,267]. Hub proteins aregenerally highly enriched with minimotifs, and our reviewconsolidates many types of minimotifs involved in familialNDs. Hub nodes can collapse an entire network because offunctional overload and ability to redistribute informationflow [268].
� 25 July 2018 � 9:16 am � ce
web4C=FPO
web4C=FPO
Fig. 1. General Q18functions of minimotifs in NDs. Minimotifs perform multiple functions in NDs. Shown here are a selected functions or cell processes of
minimotifs in NDs. Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CJ, Creutzfeldt-Jakob; FTD, frontotemporal dementia;
HD, Huntington’s disease; NCL, neuronal ceroid lipofuscinosis; PD, Parkinson’s disease; RP, retinitis pigmentosa; SBMA, spinal and bulbar muscular atrophy;
SA, spinocerebellar ataxia.
web4C=FPO
web4C=FPO
Fig. 2. Minimotifs in neurotoxic protein aggregation. The different types of
aggregates in NDs are shown. The types of minimotifs for each aggregate
are binding (B), trafficking (T), and posttranslational modification (M).Q19 Ab-
breviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis;
CJ, Creutzfeldt-Jakob; FTD, frontotemporal dementia; HD, Huntington’s
disease; NCL, neuronal ceroid lipofuscinosis; PD, Parkinson’s disease;
RP, retinitis pigmentosa; SBMA, spinal and bulbar muscular atrophy; SA,
spinocerebellar ataxia.
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In sporadic NDs, GWAS studies have helped resolve anetiology of the culmination of many genetic variants of smalleffect size. In this scenario, we suggest that this networkdysfunction arises from a dynamic redistribution of flowthrough the network [267]. The genetic risk score is a mea-sure of reaching a mutational burden threshold and is consis-tent with this model. While many of the variants are innoncoding regions, disruption of key minimotifs likely con-tributes to the network dysfunction. Furthermore, the birth ofbillions of people provides a screen to identify how multiplevariants can contribute to breaking network robustness man-ifested as NDs. This could also explain the higher prevalenceof sporadic disease in general.
The role of minimotifs in network dysfunction may alsoprovide an explanation for the slow progression of NDs,often over decades. ND can be considered a cascading fail-ure of networks where several models have been proposed.For late-onset AD, the uncontrolled neuroinflammation hy-pothesis proposes a feedback cycle that leads to shutdownof microglial phagocytosis of amyloid plaques [269–271].This is an example of a cascading failure of a networkwhere the disease manifest once a key threshold isbreached with overload of a subnet [272]. Minimotifs areinvolved in immune responses and autophagy and are likelypart of the network dysfunction [273].
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In conclusion, our summarization of NDs shows a perva-sive role for many different types of minimotifs in familialmutations, aggregation, the histone code, epigenetics, andbiomarkers. Minimotifs are likely a key part of networkdysfunction in NDs.
Acknowledgments
The National Institutes of Health grants R15GM107983,R01GM079689, R01LM010101, R21AI116411, andP20GM121325 was provided to M.R.S., P20GM109025and NV Governor’s Office of Economic DevelopmentKnowledge Fund awarded to M.R.S; U54GM104944 toJ.C.C., R01MH101054 to X.N.C., and R01MH109706 toE.C.O.; supported this work. The National Institutes of Gen-eral Medical Sciences (NIGMS) supports research infra-structure through Institutional Development Awards(IDeAs) and Center of Biomedical Research Excellence(COBRE) awards. This work stems from a collaborationof the Nevada Institute of Personalized Medicine (NIPM)and the Center for Neurodegeneration and TranslationalNeuroscience (CNTN). The collaboration is based on CO-BRE awards to the Cleveland Clinic Lou Ruvo Center forBrain Health and the University of Nevada Las Vegas(UNLV).
Uncited figure and references
Figs. 1 and 2; [298-302].
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RESEARCH IN CONTEXT
1. Systematic review: ---.
2. Interpretation: ---.
3. Future directions---.
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References
[1] Balla S, Thapar V, Verma S, Luong T, Faghri T, Huang CH, et al. Min-
imotif Miner: a tool for investigating protein function. Nat Methods
2006;3:175–7.
[2] Mi T, Merlin JC, Deverasetty S, Gryk MR, Bill TJ, Brooks AW, et al.
Minimotif Miner 3.0: database expansion and significantly improved
reduction of false-positive predictions from consensus sequences.
Nucleic Acids Res 2012;40:D252–60.
[3] Rajasekaran S, Balla S, Gradie P, Gryk MR, Kadaveru K, Kundeti V,
et al. Minimotif miner 2nd release: a database and web system for
motif search. Nucleic Acids Res 2009;37:D185–90.
[4] Lyon KF, Cai X, Young RJ, Mamun A-A, Rajasekaran S,
Schiller MR. Minimotif Miner 4: a million peptide minimotifs and
counting. Nucleic Acids Res 2018;46:D465–70.
FLA 5.5.0 DTD � TRCI168_proof
[5] Dinkel H, Van Roey K, Michael S, Kumar M, Uyar B, Altenberg B,
et al. ELM 2016-data update and new functionality of the eukaryotic
linear motif resource. Nucleic Acids Res 2016;44:D294–300.
[6] Tompa P, Davey NE, Gibson TJ, BabuMM. A million peptide motifs
for the molecular biologist. Mol Cell 2014;55:161–9.
[7] Lyon KF, Strong CL, Schooler SG, Young RJ, Roy N, Ozar B, et al.
Natural variability of minimotifs in 1092 people indicates that
minimotifs are targets of evolution. Nucleic Acids Res 2015;
43:6399–412. Q
[8] Reimand J, Wagih O, Bader GD. Evolutionary constraint and disease
associations of post-translational modification sites in human
genomes. PLoS Genet 2015;11:e1004919.
[9] Uyar B, Weatheritt RJ, Dinkel H, Davey NE, Gibson TJ. Proteome-
wide analysis of human disease mutations in short linear motifs:
neglected players in cancer? Mol Biosyst 2014;10:2626–42.
[10] Sobhy H. A review of functional motifs utilized by viruses.
Proteomes 2016;4. Q
[11] Kadaveru K, Vyas J, Schiller MR. Viral infection and human disease-
insights from minimotifs. Front Biosci 2008;13:6455–71.
[12] Choong NW, Cohen EEW. Forthcoming receptor tyrosine kinase
inhibitors. Expert Opin Ther Targets 2006;10:793–7.
[13] Przedborski S, Vila M, Jackson-Lewis V. Neurodegeneration: what is
it and where are we? J Clin Invest 2003;111:3–10.
[14] Montecchi-Palazzi L, Beavis R, Binz P-A, Chalkley RJ, Cottrell J,
Creasy D, et al. The PSI-MOD community standard for representa-
tion of protein modification data. Nat Biotechnol 2008;26:864–6.
[15] Schachter H. The joys of HexNAc. The synthesis and function of
N- and O-glycan branches. Glycoconj J 2000;17:465–83.
[16] Yan A, Lennarz WJ. Unraveling the mechanism of protein N-glyco-
sylation. J Biol Chem 2005;280:3121–4.
[17] Ohtsubo K, Marth JD. Glycosylation in cellular mechanisms of
health and disease. Cell 2006;126:855–67.
[18] Sol�a RJ, Griebenow K. Effects of glycosylation on the stability of
protein pharmaceuticals. J Pharm Sci 2009;98:1223–45.
[19] Grasbon-Frodl E, Lorenz H, Mann U, Nitsch RM, Windl O,
Kretzschmar HA. Loss of glycosylation associated with the T183A
mutation in human prion disease. Acta Neuropathol 2004;
108:476–84.
[20] Otvos L, Cudic M. Post-translational modifications in prion proteins.
Curr Protein Pept Sci 2002;3:643–52.
[21] Ermonval M, Mouillet-Richard S, Codogno P, Kellermann O, Botti J.
Evolving views in prion glycosylation: functional and pathological
implications. Biochimie 2003;85:33–45.
[22] DeArmond SJ, S�anchez H, Yehiely F, Qiu Y, Ninchak-Casey A,
Daggett V, et al. Selective neuronal targeting in prion disease. Neuron
1997;19:1337–48.
[23] Giuliano F, Bannwarth S, Monnot S, Cano A, Chabrol B, Vialettes B,
et al. Wolfram syndrome in French population: characterization of
novel mutations and polymorphisms in the WFS1 gene. Hum Mutat
2005;25:99–100.
[24] Meli M, Gasset M, Colombo G. Dynamic diagnosis of familial prion
diseases supports the b2-a2 loop as a Universal Interference Target.
PLoS ONE 2011;6:e19093.
[25] Cheng CJ, Daggett V. Different misfolding mechanisms converge on
common conformational changes: human prion protein pathogenic
mutants Y218N and E196K. Prion 2014;8:125–35.
[26] Gizaw ST, Koda T, AmanoM, KamimuraK, Ohashi T, HinouH, et al.
A comprehensive glycome profiling of Huntington’s disease trans-
genic mice. Biochim Biophys Acta 2015;1850:1704–18.
[27] Abou-Abbass H, Abou-El-Hassan H, BahmadH, Zibara K, Zebian A,
Youssef R, et al. Glycosylation and other PTMs alterations in neuro-
degenerative diseases: Current status and future role in neurotrauma.
Electrophoresis 2016;37:1549–61.
[28] Silveyra M-X, Cuadrado-Corrales N, Marcos A, Barquero M-S,
R�abano A, Calero M, et al. Altered glycosylation of acetylcholines-
terase in Creutzfeldt-Jakob disease. J Neurochem 2006;96:97–104.
� 25 July 2018 � 9:16 am � ce
1583
S. Sharma et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19 13
1584
1585
1586
1587
1588
1589
1590
1591
1592
1593
1594
1595
1596
1597
1598
1599
1600
1601
1602
1603
1604
1605
1606
1607
1608
1609
1610
1611
1612
1613
1614
1615
1616
1617
1618
1619
1620
1621
1622
1623
1624
1625
1626
1627
1628
1629
1630
1631
1632
1633
1634
1635
1636
1637
1638
1639
1640
1641
1642
1643
1644
1645
1646
1647
1648
1649
1650
1651
1652
1653
1654
1655
1656
1657
1658
1659
1660
1661
1662
1663
1664
1665
1666
1667
1668
1669
1670
1671
1672
1673
1674
1675
1676
1677
1678
1679
1680
1681
1682
1683
1684
1685
1686
1687
1688
1689
1690
1691
1692
1693
1694
1695
1696
1697
1698
1699
1700
1701
1702
1703
1704
1705
1706
1707
1708
1709
1710
1711
1712
1713
1714
1715
1716
[29] Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, et al.
Glycated tau protein in Alzheimer disease: a mechanism for induc-
tion of oxidant stress. Proc Natl Acad Sci U S A 1994;91:7787–91.
[30] Liu F, Zaidi T, Iqbal K, Grundke-Iqbal I, Gong C-X. Aberrant glyco-
sylation modulates phosphorylation of tau by protein kinase A and
dephosphorylation of tau by protein phosphatase 2A and 5. Neurosci-
ence 2002;115:829–37.
[31] Sato Y, Naito Y, Grundke-Iqbal I, Iqbal K, Endo T. Analysis of N-gly-
cans of pathological tau: possible occurrence of aberrant processing
of tau in Alzheimer’s disease. FEBS Lett 2001;496:152–60.
[32] Hock E-M, Polymenidou M. Prion-like propagation as a pathogenic
principle in frontotemporal dementia. J Neurochem 2016;138 Suppl
1:163–83.
[33] Gong C-X, Iqbal K. Hyperphosphorylation of microtubule-
associated protein tau: a promising therapeutic target for Alzheimer
disease. Curr Med Chem 2008;15:2321–8.
[34] Wang J-Z, Xia Y-Y, Grundke-Iqbal I, Iqbal K. Abnormal hyperphos-
phorylation of tau: sites, regulation, and molecular mechanism of
neurofibrillary degeneration. J Alzheimers Dis 2013;33 Suppl
1:S123–39.
[35] Sj€ogren M, Davidsson P, Tullberg M, Minthon L, Wallin A,
Wikkelso C, et al. Both total and phosphorylated tau are increased
in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2001;
70:624–30.
[36] Hampel H, Teipel SJ. Total and phosphorylated tau proteins: evalua-
tion as core biomarker candidates in frontotemporal dementia. De-
ment Geriatr Cogn Disord 2004;17:350–4.
[37] Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K,
Caccavello RJ, et al. Phosphorylation of Ser-129 is the dominant
pathological modification of alpha-synuclein in familial and sporadic
Lewy body disease. J Biol Chem 2006;281:29739–52.
[38] Tenreiro S, Eckermann K, Outeiro TF. Protein phosphorylation in
neurodegeneration: friend or foe? Front Mol Neurosci 2014;7:42.
[39] Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E,
Goldberg MS, et al. alpha-Synuclein is phosphorylated in synuclein-
opathy lesions. Nat Cell Biol 2002;4:160–4.
[40] Qing H, Wong W, McGeer EG, McGeer PL. Lrrk2 phosphorylates
alpha synuclein at serine 129: Parkinson disease implications. Bio-
chem Biophys Res Commun 2009;387:149–52.
[41] Inglis KJ, Chereau D, Brigham EF, Chiou S-S, Sch€obel S, Frigon NL,
et al. Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at
serine 129 in central nervous system. J Biol Chem 2009;
284:2598–602.
[42] Okochi M,Walter J, Koyama A, Nakajo S, BabaM, Iwatsubo T, et al.
Constitutive phosphorylation of the Parkinson’s disease associated
alpha-synuclein. J Biol Chem 2000;275:390–7.
[43] Pronin AN, Morris AJ, Surguchov A, Benovic JL. Synucleins are a
novel class of substrates for G protein-coupled receptor kinases. J
Biol Chem 2000;275:26515–22.
[44] Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H,
Spooren W, et al. Hyperphosphorylation and insolubility of alpha-
synuclein in transgenic mouse oligodendrocytes. EMBO Rep
2002;3:583–8.
[45] Paleologou KE, Oueslati A, Shakked G, Rospigliosi CC, Kim H-Y,
Lamberto GR, et al. Phosphorylation at S87 is enhanced in synuclei-
nopathies, inhibits alpha-synuclein oligomerization, and influences
synuclein-membrane interactions. J Neurosci 2010;30:3184–98.
[46] Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB,
Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson’s
disease: comprehensive screening in publicly available cases and
control. J Med Genet 2009;46:375–81.
[47] Sha D, Chin L-S, Li L. Phosphorylation of parkin by Parkinson
disease-linked kinase PINK1 activates parkin E3 ligase function
and NF-kB signaling. Hum Mol Genet 2010;19:352–63.
[48] Kazlauskaite A, Kelly V, Johnson C, Baillie C, Hastie CJ, Peggie M,
et al. Phosphorylation of Parkin at Serine65 is essential for activation:
FLA 5.5.0 DTD � TRCI168_proof
elaboration of a Miro1 substrate-based assay of Parkin E3 ligase ac-
tivity. Open Biol 2014;4:130213.
[49] Dawson TM, Dawson VL. The role of parkin in familial and sporadic
Parkinson’s disease. Mov Disord 2010;25 Suppl 1:S32–9.
[50] Piccoli G, Onofri F, Cirnaru MD, Kaiser CJO, Jagtap P,
Kastenm€uller A, et al. Leucine-rich repeat kinase 2 binds to neuronal
vesicles through protein interactions mediated by its C-terminal
WD40 domain. Mol Cell Biol 2014;34:2147–61.
[51] Zoghbi HY, Orr HT. Pathogenic mechanisms of a polyglutamine-
mediated neurodegenerative disease, spinocerebellar ataxia type 1.
J Biol Chem 2009;284:7425–9.
[52] Chen H-K, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD,
Fernandez MH, et al. Interaction of Akt-phosphorylated ataxin-1
with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia
type 1. Cell 2003;113:457–68.
[53] FayJM,ZhuC,ProctorEA,TaoY,CuiW,KeH,etal.Aphosphomimeticmu-
tationstabilizesSOD1andrescuescellviabilityinthecontextofanALS-
associatedmutation.Structure2016;24:1898–906.
[54] Resh MD. Targeting protein lipidation in disease. Trends Mol Med
2012;18:206–14.
[55] Lemonidis K, Sanchez-Perez MC, Chamberlain LH. Identification of
a novel sequence motif recognized by the ankyrin repeat domain of
zDHHC17/13 S-Acyltransferases. J Biol Chem 2015;290:21939–50.
[56] Tsutsumi R, Fukata Y, Fukata M. Discovery of protein-
palmitoylating enzymes. Pflugers Arch 2008;456:1199–206.
[57] Fukata Y, Fukata M. Protein palmitoylation in neuronal development
and synaptic plasticity. Nat Rev Neurosci 2010;11:161–75.
[58] Young FB, Butland SL, Sanders SS, Sutton LM, HaydenMR. Putting
proteins in their place: palmitoylation in Huntington disease and
other neuropsychiatric diseases. Prog Neurobiol 2012;97:220–38.
[59] Hornemann T. Palmitoylation and depalmitoylation defects. J Inherit
Metab Dis 2015;38:179–86.
[60] Fukata M, Fukata Y, Adesnik H, Nicoll RA, Bredt DS. Identification
of PSD-95 palmitoylating enzymes. Neuron 2004;44:987–96.
[61] Cho E, Park M. Palmitoylation in Alzheimer’s disease and other
neurodegenerative diseases. Pharmacol Res 2016;111:133–51.
[62] Martin DDO, Hayden MR. Post-translational myristoylation at the
cross roads of cell death, autophagy and neurodegeneration. Biochem
Soc Trans 2015;43:229–34.
[63] Valle C, Carr�ı MT. Cysteine modifications in the pathogenesis of
ALS. Front Mol Neurosci 2017;10:5.
[64] Antinone SE, Ghadge GD, Lam TT, Wang L, Roos RP, Green WN.
Palmitoylation of superoxide dismutase 1 (SOD1) is increased for fa-
milial amyotrophic lateral sclerosis-linked SOD1 mutants. J Biol
Chem 2013;288:21606–17.
[65] Choi J, Rees HD,Weintraub ST, Levey AI, Chin L-S, Li L. Oxidative
modifications and aggregation of Cu,Zn-superoxide dismutase asso-
ciated with Alzheimer and Parkinson diseases. J Biol Chem 2005;
280:11648–55.
[66] Greaves J, Lemonidis K, Gorleku OA, Cruchaga C, Grefen C,
Chamberlain LH. Palmitoylation-induced aggregation of cysteine-
string protein mutants that cause neuronal ceroid lipofuscinosis. J
Biol Chem 2012;287:37330–9.
[67] Fantini J, Yahi N. Molecular basis for the glycosphingolipid-binding
specificity of a-synuclein: key role of tyrosine 39 in membrane inser-
tion. J Mol Biol 2011;408:654–69.
[68] Fantini J, Carlus D, Yahi N. The fusogenic tilted peptide (67-78) of a-
synuclein is a cholesterol binding domain. Biochim Biophys Acta
2011;1808:2343–51.
[69] Okada T, Wakabayashi M, Ikeda K, Matsuzaki K. Formation of toxic
fibrils of Alzheimer’s amyloid beta-protein-(1-40) by monosialogan-
glioside GM1, a neuronal membrane component. J Mol Biol 2007;
371:481–9.
[70] Martinez Z, Zhu M, Han S, Fink AL. GM1 specifically interacts with
alpha-synuclein and inhibits fibrillation. Biochemistry 2007;
46:1868–77.
� 25 July 2018 � 9:16 am � ce
1717
S. Sharma et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-1914
1718
1719
1720
1721
1722
1723
1724
1725
1726
1727
1728
1729
1730
1731
1732
1733
1734
1735
1736
1737
1738
1739
1740
1741
1742
1743
1744
1745
1746
1747
1748
1749
1750
1751
1752
1753
1754
1755
1756
1757
1758
1759
1760
1761
1762
1763
1764
1765
1766
1767
1768
1769
1770
1771
1772
1773
1774
1775
1776
1777
1778
1779
1780
1781
1782
1783
1784
1785
1786
1787
1788
1789
1790
1791
1792
1793
1794
1795
1796
1797
1798
1799
1800
1801
1802
1803
1804
1805
1806
1807
1808
1809
1810
1811
1812
1813
1814
1815
1816
1817
1818
1819
1820
1821
1822
1823
1824
1825
1826
1827
1828
1829
1830
1831
1832
1833
1834
1835
1836
1837
1838
1839
1840
1841
1842
1843
1844
1845
1846
1847
1848
1849
1850
1851
[71] Jamin N, Neumann J-M, Ostuni MA, Vu TKN, Yao Z-X, Murail S,
et al. Characterization of the cholesterol recognition amino acid
consensus sequence of the peripheral-type benzodiazepine receptor.
Mol Endocrinol 2005;19:588–94.
[72] Hottman DA, Li L. Protein prenylation and synaptic plasticity: impli-
cations for Alzheimer’s disease. Mol Neurobiol 2014;50:177–85.
[73] MattsonMP. Methylation and acetylation in nervous system develop-
ment and neurodegenerative disorders. Ageing Res Rev 2003;
2:329–42.
[74] Drazic A, Myklebust LM, Ree R, Arnesen T. The world of protein
acetylation. Biochim Biophys Acta 2016;1864:1372–401.
[75] Thomas SN, Funk KE, Wan Y, Liao Z, Davies P, Kuret J, et al. Dual
modification of Alzheimer’s disease PHF-tau protein by lysine
methylation and ubiquitylation: a mass spectrometry approach.
Acta Neuropathol 2012;123:105–17.
[76] Min S-W, Cho S-H, Zhou Y, Schroeder S, Haroutunian V,
Seeley WW, et al. Acetylation of tau inhibits its degradation and con-
tributes to tauopathy. Neuron 2010;67:953–66.
[77] Min S-W, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, et al. Critical
role of acetylation in tau-mediated neurodegeneration and cognitive
deficits. Nat Med 2015;21:1154–62.
[78] Trexler AJ, Rhoades E. N-Terminal acetylation is critical for forming
a-helical oligomer of a-synuclein. Protein Sci 2012;21:601–5.
[79] Bartels T, Kim NC, Luth ES, Selkoe DJ. N-alpha-acetylation of a-
synuclein increases its helical folding propensity, GM1 binding spec-
ificity and resistance to aggregation. PLoS One 2014;9:e103727.
[80] Arnesen T, Starheim KK, Van Damme P, Evjenth R, Dinh H,
Betts MJ, et al. The chaperone-like protein HYPK acts together
with NatA in cotranslational N-terminal acetylation and prevention
of Huntingtin aggregation. Mol Cell Biol 2010;30:1898–909.
[81] AsaumiM, IijimaK, Sumioka A, Iijima-AndoK, KirinoY, Nakaya T,
et al. Interaction of N-terminal acetyltransferasewith the cytoplasmic
domain of beta-amyloid precursor protein and its effect on A beta
secretion. J Biochem 2005;137:147–55.
[82] Holmes WM, Mannakee BK, Gutenkunst RN, Serio TR. Loss of
amino-terminal acetylation suppresses a prion phenotype by modu-
lating global protein folding. Nat Commun 2014;5:4383.
[83] Pritzker LB, Joshi S, Harauz G, Moscarello MA. Deimination of
myelin basic protein. 2. Effect of methylation of MBP on its deimina-
tion by peptidylarginine deiminase. Biochemistry 2000;39:5382–8.
[84] Gu L, Robinson RAS. Proteomic approaches to quantify cysteine
reversible modifications in aging and neurodegenerative diseases.
Proteomics Clin Appl 2016;10:1159–77.
[85] Dr€ogeW. Oxidative stress and ageing: is ageing a cysteine deficiency
syndrome? Philos Trans R Soc Lond B Biol Sci 2005;360:2355–72.
[86] Li J, OW, LiW, Jiang Z-G, Ghanbari HA. Oxidative stress and neuro-
degenerative disorders. Int J Mol Sci 2013;14:24438–75.
[87] Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor
neuron injury and therapeutic target. Free Radic Biol Med 2010;
48:629–41.
[88] Furukawa Y, O’Halloran TV. Posttranslational modifications in
Cu,Zn-superoxide dismutase and mutations associated with amyotro-
phic lateral sclerosis. Antioxid Redox Signal 2006;8:847–67.
[89] McAlary L, Yerbury JJ, Aquilina JA. Glutathionylation potentiates
benign superoxide dismutase 1 variants to the toxic forms associated
with amyotrophic lateral sclerosis. Sci Rep 2013;3:3275.
[90] Wilcox KC, Zhou L, Jordon JK, Huang Y, Yu Y, Redler RL, et al.
Modifications of superoxide dismutase (SOD1) in human erythro-
cytes: a possible role in amyotrophic lateral sclerosis. J Biol Chem
2009;284:13940–7.
[91] Nakamura T, Tu S, AkhtarMW, Sunico CR, Okamoto S-I, Lipton SA.
Aberrant protein s-nitrosylation in neurodegenerative diseases.
Neuron 2013;78:596–614.
[92] Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER,
Floyd RA, et al. Excess brain protein oxidation and enzyme dysfunc-
tion in normal aging and in Alzheimer disease. Proc Natl Acad Sci U
S A 1991;88:10540–3.
FLA 5.5.0 DTD � TRCI168_proof
[93] Danielson SR, Andersen JK. Oxidative and nitrative protein modifi-
cations in Parkinson’s disease. Free Radic Biol Med 2008;
44:1787–94.
[94] Giasson BI, Ischiropoulos H, Lee VM-Y, Trojanowski JQ. The rela-
tionship between oxidative/nitrative stress and pathological inclu-
sions in Alzheimer’s and Parkinson’s diseases. Free Radic Biol
Med 2002;32:1264–75.
[95] Stamler JS, Toone EJ, Lipton SA, Sucher NJ. (S)NO signals: translo-
cation, regulation, and a consensus motif. Neuron 1997;18:691–6.
[96] Stamler JS. Redox signaling: nitrosylation and related target interac-
tions of nitric oxide. Cell 1994;78:931–6.
[97] Nakamura T, Lipton SA. S-Nitrosylation and uncompetitive/fast off-
rate (UFO) drug therapy in neurodegenerative disorders of protein
misfolding. Cell Death Differ 2007;14:1305–14.
[98] Dantuma NP, Bott LC. The ubiquitin-proteasome system in neurode-
generative diseases: precipitating factor, yet part of the solution.
Front Mol Neurosci 2014;7:70.
[99] Shimura H, Schlossmacher MG, Hattori N, Frosch MP,
Trockenbacher A, Schneider R, et al. Ubiquitination of a new form
of alpha-synuclein by parkin from human brain: implications for Par-
kinson’s disease. Science 2001;293:263–9.
[100] Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, et al. Par-
kin ubiquitinates the alpha-synuclein-interacting protein, synphilin-
1: implications for Lewy-body formation in Parkinson disease. Nat
Med 2001;7:1144–50.
[101] Wang GP, Khatoon S, Iqbal K, Grundke-Iqbal I. Brain ubiquitin is
markedly elevated in Alzheimer disease. Brain Res 1991;
566:146–51.
[102] Kurita K, Manaka H, Kato T, Katagiri T, Sasaki H. [A case of
Creutzfeldt-Jakob diseasewith markedly elevated ubiquitin concentra-
tion in the cerebrospinal fluid]. Rinsho Shinkeigaku 1991;31:666–8.
[103] Kang S, Hong S. Molecular pathogenesis of spinocerebellar ataxia
type 1 disease. Mol Cells 2009;27:621–7.
[104] Shibata H, Huynh DP, Pulst SM. A novel protein with RNA-binding
motifs interacts with ataxin-2. Hum Mol Genet 2000;9:1303–13.
[105] McFadden K, Hamilton RL, Insalaco SJ, Lavine L, Al-Mateen M,
WangG, et al. Neuronal intranuclear inclusion diseasewithout polyglut-
amine inclusions in a child. J Neuropathol ExpNeurol 2005;64:545–52.
[106] Nath SR, Lieberman AP. The ubiquitination, disaggregation and pro-
teasomal degradation machineries in polyglutamine disease. Front
Mol Neurosci 2017;10:78.
[107] Sambataro F, Pennuto M. Post-translational modifications and pro-
tein quality control in motor neuron and polyglutamine diseases.
Front Mol Neurosci 2017;10:82.
[108] Gray KM, Kaifer KA, Baillat D,Wen Y, Bonacci TR, Ebert AD, et al.
Self-oligomerization regulates stability of Survival Motor Neuron
(SMN) protein isoforms by sequestering an SCFSlmb degron. Mol
Biol Cell 2018;29:96–110.
[109] Burnett BG, Mu~noz E, Tandon A, Kwon DY, Sumner CJ,
Fischbeck KH. Regulation of SMN protein stability. Mol Cell Biol
2009;29:1107–15.
[110] Yang Y, He Y, Wang X, Liang Z, He G, Zhang P, et al. Protein SU-
MOylation modification and its associations with disease. Open
Biol 2017;7.
[111] Anderson DB, Zanella CA, Henley JM, Cimarosti H. Sumoylation:
implications for neurodegenerative diseases. Adv Exp Med Biol
2017;963:261–81.
[112] Dorval V, Fraser PE. SUMO on the road to neurodegeneration. Bio-
chim Biophys Acta 2007;1773:694–706.
[113] Hoppe JB, Salbego CG, Cimarosti H. SUMOylation: novel neuropro-
tective approach for Alzheimer’s disease? Aging Dis 2015;6:322–30.
[114] Lee L, Sakurai M,Matsuzaki S, Arancio O, Fraser P. SUMO and Alz-
heimer’s disease. Neuromolecular Med 2013;15:720–36.
[115] Luo H-B, Xia Y-Y, Shu X-J, Liu Z-C, Feng Y, Liu X-H, et al. SU-
MOylation at K340 inhibits tau degradation through deregulating
its phosphorylation and ubiquitination. Proc Natl Acad Sci U S A
2014;111:16586–91.
� 25 July 2018 � 9:16 am � ce
S. Sharma et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19 15
1852
1853
1854
1855
1856
1857
1858
1859
1860
1861
1862
1863
1864
1865
1866
1867
1868
1869
1870
1871
1872
1873
1874
1875
1876
1877
1878
1879
1880
1881
1882
1883
1884
1885
1886
1887
1888
1889
1890
1891
1892
1893
1894
1895
1896
1897
1898
1899
1900
1901
1902
1903
1904
1905
1906
1907
1908
1909
1910
1911
1912
1913
1914
1915
1916
1917
1918
1919
1920
1921
1922
1923
1924
1925
1926
1927
1928
1929
1930
1931
1932
1933
1934
1935
1936
1937
1938
1939
1940
1941
1942
1943
1944
1945
1946
1947
1948
1949
1950
1951
1952
1953
1954
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
[116] Kontaxi C, Piccardo P, Gill AC. Lysine-directed post-translational
modifications of tau protein in Alzheimer’s disease and related tauo-
pathies. Front Mol Biosci 2017;4:56.
[117] Krumova P, Meulmeester E, Garrido M, Tirard M, Hsiao H-H,
Bossis G, et al. Sumoylation inhibits a-synuclein aggregation and
toxicity. J Cell Biol 2011;194:49–60.
[118] Kunadt M, Eckermann K, Stuendl A, Gong J, Russo B, Strauss K,
et al. Extracellular vesicle sorting of a-Synuclein is regulated by su-
moylation. Acta Neuropathol 2015;129:695–713.
[119] Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC,
Slepko N, et al. SUMO modification of Huntingtin and Huntington’s
disease pathology. Science 2004;304:100–4.
[120] Dangoumau A, Marouillat S, Burlaud Gaillard J, Uzbekov R, Veyrat-
Durebex C, Blasco H, et al. Inhibition of pathogenic mutant SOD1
aggregation in cultured motor neuronal cells by prevention of its SU-
MOylation on Lysine 75. Neurodegener Dis 2016;16:161–71.
[121] Dangoumau A, Veyrat-Durebex C, Blasco H, Praline J, Corcia P,
Andres CR, et al. Protein SUMOylation, an emerging pathway in
amyotrophic lateral sclerosis. Int J Neurosci 2013;123:366–74.
[122] Niikura T, Kita Y, Abe Y. SUMO3 modification accelerates the
aggregation of ALS-linked SOD1 mutants. PLoS One 2014;
9:e101080.
[123] Wang T, Xu W, Qin M, Yang Y, Bao P, Shen F, et al. Pathogenic mu-
tations in the valosin-containing protein/p97(VCP) N-domain Inhibit
the SUMOylation of VCP and lead to impaired stress response. J Biol
Chem 2016;291:14373–84.
[124] MoscarelloMA,Mastronardi FG,Wood DD. The role of citrullinated
proteins suggests a novel mechanism in the pathogenesis of multiple
sclerosis. Neurochem Res 2007;32:251–6.
[125] Jang B, Ishigami A, Maruyama N, Carp RI, Kim Y-S, Choi E-K. Pep-
tidylarginine deiminase and protein citrullination in prion diseases:
strong evidence of neurodegeneration. Prion 2013;7:42–6.
[126] Ishigami A, Ohsawa T, Hiratsuka M, Taguchi H, Kobayashi S,
Saito Y, et al. Abnormal accumulation of citrullinated proteins
catalyzed by peptidylarginine deiminase in hippocampal extracts
from patients with Alzheimer’s disease. J Neurosci Res 2005;
80:120–8.
[127] Nicholas AP. Dual immunofluorescence study of citrullinated pro-
teins in Parkinson diseased substantia nigra. Neurosci Lett 2011;
495:26–9.
[128] Jang B, Jeon Y-C, Choi J-K, Park M, Kim J-I, Ishigami A, et al. Pep-
tidylarginine deiminase modulates the physiological roles of enolase
via citrullination: links between altered multifunction of enolase and
neurodegenerative diseases. Biochem J 2012;445:183–92.
[129] Acharya NK, Nagele EP, Han M, Coretti NJ, DeMarshall C,
Kosciuk MC, et al. Neuronal PAD4 expression and protein citrullina-
tion: possible role in production of autoantibodies associated with
neurodegenerative disease. J Autoimmun 2012;38:369–80.
[130] Yang L, Tan D, Piao H.Myelin basic protein citrullination in multiple
sclerosis: a potential therapeutic target for the pathology. Neurochem
Res 2016;41:1845–56.
[131] Kim JK, Mastronardi FG, Wood DD, Lubman DM, Zand R,
Moscarello MA. Multiple sclerosis: an important role for post-
translational modifications of myelin basic protein in pathogenesis.
Mol Cell Proteomics 2003;2:453–62.
[132] Ciechanover A, Kwon YT. Degradation of misfolded proteins in
neurodegenerative diseases: therapeutic targets and strategies. Exp
Mol Med 2015;47:e147.
[133] Wilson CM, Mushtaq G, Kamal MA, Terro F. The Role of endopro-
teolytic processing in neurodegeneration. CNS Neurol Disord Drug
Targets 2016;15:1222–30.
[134] Marcelli S, CorboM, Iannuzzi F, Negri L, Blandini F, Nistic�o R, et al.
The involvement of post-translational modifications in Alzheimer’s
disease. Curr Alzheimer Res 2018;15:313–35.
[135] Wang X, Zhou X, Li G, Zhang Y, Wu Y, Song W. Modifications and
trafficking of APP in the pathogenesis of Alzheimer’s disease. Front
Mol Neurosci 2017;10:294.
FLA 5.5.0 DTD � TRCI168_proof
[136] Vidal R, Frangione B, Rostagno A, Mead S, R�ev�esz T, Plant G, et al.
A stop-codon mutation in the BRI gene associated with familial
British dementia. Nature 1999;399:776–81.
[137] Kim SH, Wang R, Gordon DJ, Bass J, Steiner DF, Lynn DG, et al.
Furin mediates enhanced production of fibrillogenic ABri peptides
in familial British dementia. Nat Neurosci 1999;2:984–8.
[138] Kim S-H, Creemers JWM, Chu S, Thinakaran G, Sisodia SS. Proteo-
lytic processing of familial British dementia-associated BRI variants:
evidence for enhanced intracellular accumulation of amyloidogenic
peptides. J Biol Chem 2002;277:1872–7.
[139] Kim SH,Wang R, GordonDJ, Bass J, Steiner DF, ThinakaranG, et al.
Familial British dementia: expression and metabolism of BRI. Ann N
YAcad Sci 2000;920:93–9.
[140] Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, et al. Caspase 3-
cleaved N-terminal fragments of wild-type and mutant huntingtin are
present in normal and Huntington’s disease brains, associate with
membranes, and undergo calpain-dependent proteolysis. Proc Natl
Acad Sci U S A 2001;98:12784–9.
[141] Sun B, Fan W, Balciunas A, Cooper JK, Bitan G, Steavenson S, et al.
Polyglutamine repeat length-dependent proteolysis of huntingtin.
Neurobiol Dis 2002;11:111–22.
[142] Landles C, Sathasivam K, Weiss A, Woodman B, Moffitt H,
Finkbeiner S, et al. Proteolysis of mutant huntingtin produces an
exon 1 fragment that accumulates as an aggregated protein in
neuronal nuclei in Huntington disease. J Biol Chem 2010;
285:8808–23.
[143] Miller JP, Holcomb J, Al-Ramahi I, de Haro M, Gafni J, Zhang N,
et al. Matrix metalloproteinases are modifiers of huntingtin proteoly-
sis and toxicity in Huntington’s disease. Neuron 2010;67:199–212.
[144] Ratovitski T, Chighladze E, Waldron E, Hirschhorn RR, Ross CA.
Cysteine proteases bleomycin hydrolase and cathepsin Z mediate
N-terminal proteolysis and toxicity of mutant huntingtin. J Biol
Chem 2011;286:12578–89.
[145] Wang X, Huang T, Bu G, Xu H. Dysregulation of protein trafficking
in neurodegeneration. Mol Neurodegener 2014;9:31.
[146] Sharma S, Toledo O, Hedden M, Lyon KF, Brooks SB, David RP,
et al. The Functional Human C-Terminome. PLoS One 2016;
11:e0152731.
[147] Schreij AMA, Fon EA, McPherson PS. Endocytic membrane traf-
ficking and neurodegenerative disease. Cell Mol Life Sci 2016;
73:1529–45.
[148] Abeliovich A, Gitler AD. Defects in trafficking bridge Parkinson’s
disease pathology and genetics. Nature 2016;539:207–16.
[149] Hasegawa T, Sugeno N, Kikuchi A, Baba T, Aoki M. Membrane traf-
ficking illuminates a path to Parkinson’s disease. Tohoku J Exp Med
2017;242:63–76.
[150] Esposito G, Ana Clara F, Verstreken P. Synaptic vesicle trafficking
and Parkinson’s disease. Dev Neurobiol 2012;72:134–44.
[151] Hunn BHM, Cragg SJ, Bolam JP, Spillantini M-G, Wade-Martins R.
Impaired intracellular trafficking defines early Parkinson’s disease.
Trends Neurosci 2015;38:178–88.
[152] Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U,
et al. Web-based genome-wide association study identifies two novel
loci and a substantial genetic component for Parkinson’s disease.
PLoS Genet 2011;7:e1002141.
[153] Martin I, Kim JW, Dawson VL, Dawson TM. LRRK2 pathobiology
in Parkinson’s disease. J Neurochem 2014;131:554–65.
[154] Matta S, Van Kolen K, da Cunha R, van den Bogaart G,
Mandemakers W, Miskiewicz K, et al. LRRK2 controls an EndoA
phosphorylation cycle in synaptic endocytosis. Neuron 2012;
75:1008–21.
[155] Park J-S, Kim D-H, Yoon S-Y. Regulation of amyloid precursor pro-
tein processing by its KFERQ motif. BMB Rep 2016;49:337–42.
[156] Wang J, Shan C, Cao W, Zhang C, Teng J, Chen J. SCG10 promotes
non-amyloidogenic processing of amyloid precursor protein by facil-
itating its trafficking to the cell surface. Hum Mol Genet 2013;
22:4888–900.
� 25 July 2018 � 9:16 am � ce
Q22
S. Sharma et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-1916
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2051
2052
2053
2054
2055
2056
2057
2058
2059
2060
2061
2062
2063
2064
2065
2066
2067
2068
2069
2070
2071
2072
2073
2074
2075
2076
2077
2078
2079
2080
2081
2082
2083
2084
2085
2086
2087
2088
2089
2090
2091
2092
2093
2094
2095
2096
2097
2098
2099
2100
2101
2102
2103
2104
2105
2106
2107
2108
2109
2110
2111
2112
2113
2114
2115
2116
2117
2118
[157] Munro S, Pelham HRB. A C-terminal signal prevents secretion of
luminal ER proteins. Cell 1987;48:899–907.
[158] Wang P, Li B, Zhou L, Fei E, Wang G. The KDEL receptor induces
autophagy to promote the clearance of neurodegenerative disease-
related proteins. Neuroscience 2011;190:43–55.
[159] Lee J, Retamal C, Cuiti~no L, Caruano-Yzermans A, Shin J-E, van
Kerkhof P, et al. Adaptor protein sorting nexin 17 regulates amyloid
precursor protein trafficking and processing in the early endosomes. J
Biol Chem 2008;283:11501–8.
[160] van Kerkhof P, Lee J, McCormick L, Tetrault E, LuW, SchoenfishM,
et al. Sorting nexin 17 facilitates LRP recycling in the early endo-
some. EMBO J 2005;24:2851–61.
[161] Paulson HL. The spinocerebellar ataxias. J Neuroophthalmol 2009;
29:227–37.
[162] Deretic D, Williams AH, Ransom N, Morel V, Hargrave PA,
Arendt A. Rhodopsin C terminus, the site of mutations causing retinal
disease, regulates trafficking by binding to ADP-ribosylation factor 4
(ARF4). Proc Natl Acad Sci USA 2005;102:3301–6.
[163] Deretic D, Schmerl S, Hargrave PA, Arendt A, McDowell JH. Regu-
lation of sorting and post-Golgi trafficking of rhodopsin by its C-ter-
minal sequence QVS(A)PA. Proc Natl Acad Sci U S A 1998;
95:10620–5.
[164] Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR,
Mehrpour M, et al. Autophagy and apoptosis dysfunction in neurode-
generative disorders. Prog Neurobiol 2014;112:24–49.
[165] Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D.
Impaired degradation of mutant alpha-synuclein by chaperone-
mediated autophagy. Science 2004;305:1292–5.
[166] Alvarez-Erviti L, Seow Y, Schapira AHV, Rodriguez-Oroz MC,
Obeso JA, Cooper JM. Influence of microRNA deregulation on
chaperone-mediated autophagy and a-synuclein pathology in Parkin-
son’s disease. Cell Death Dis 2013;4:e545.
[167] Wang Y, Martinez-Vicente M, Kr€uger U, Kaushik S, Wong E,
Mandelkow E-M, et al. Tau fragmentation, aggregation and clear-
ance: the dual role of lysosomal processing. Hum Mol Genet 2009;
18:4153–70.
[168] . Witt S, Uversky V, eds. Protein chaperones and protection from
neurodegenerative diseases. Hoboken. John Wiley & Sons; 2011.
[169] Qi L, Zhang X-D, Wu J-C, Lin F, Wang J, DiFiglia M, et al. The role
of chaperone-mediated autophagy in huntingtin degradation. PLoS
One 2012;7:e46834.
[170] Kalay E, de Brouwer APM, Caylan R, Nabuurs SB, Wollnik B,
Karaguzel A, et al. A novel D458V mutation in the SANS PDZ bind-
ing motif causes atypical Usher syndrome. J Mol Med 2005;
83:1025–32.
[171] Yan J, Pan L, ChenX,Wu L, ZhangM. The structure of the harmonin/
sans complex reveals an unexpected interaction mode of the two
Usher syndrome proteins. Proc Natl Acad Sci U S A 2010;
107:4040–5.
[172] Lee G, Thangavel R, SharmaVM, Litersky JM, Bhaskar K, Fang SM,
et al. Phosphorylation of tau by fyn: implications for Alzheimer’s dis-
ease. J Neurosci 2004;24:2304–12.
[173] Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G. Tau inter-
acts with src-family non-receptor tyrosine kinases. J Cell Sci 1998;
111:3167–77.
[174] Lee G. Tau and src family tyrosine kinases. Biochim Biophys Acta
2005;1739:323–30.
[175] Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, et al. Iden-
tification of the variant Ala335Val of MED25 as responsible for
CMT2B2: molecular data, functional studies of the SH3 recognition
motif and correlation between wild-type MED25 and PMP22 RNA
levels in CMT1A animal models. Neurogenetics 2009;10:275–87.
[176] Borg JP, Yang Y, De Tadd�eo-Borg M, Margolis B, Turner RS. The
X11alpha protein slows cellular amyloid precursor protein process-
ing and reduces Abeta40 and Abeta42 secretion. J Biol Chem
1998;273:14761–6.
FLA 5.5.0 DTD � TRCI168_proof
[177] King GD, Perez RG, Steinhilb ML, Gaut JR, Turner RS. X11alpha
modulates secretory and endocytic trafficking and metabolism of am-
yloid precursor protein: mutational analysis of the YENPTY
sequence. Neuroscience 2003;120:143–54.
[178] Ho A, Liu X, S€udhof TC. Deletion of Mint proteins decreases amy-
loid production in transgenic mouse models of Alzheimer’s disease. J
Neurosci 2008;28:14392–400.
[179] Chen H-K, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD,
Fernandez MH, et al. Interaction of Akt-phosphorylated ataxin-1
with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia
type 1. Cell 2003;113:457–68.
[180] Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM,
Hadziselimovic A, et al. The amyloid precursor protein has a flexible
transmembrane domain and binds cholesterol. Science 2012;
336:1168–71.
[181] Song Y, Hustedt EJ, Brandon S, Sanders CR. Competition between
homodimerization and cholesterol binding to the C99 domain of
the amyloid precursor protein. Biochemistry 2013;52:5051–64.
[182] Kim S, Jeon T-J, Oberai A, Yang D, Schmidt JJ, Bowie JU.
Transmembrane glycine zippers: physiological and pathological
roles in membrane proteins. Proc Natl Acad Sci U S A 2005;
102:14278–83.
[183] Knafo S, S�anchez-Puelles C, Palomer E, Delgado I, Draffin JE,
Mingo J, et al. PTEN recruitment controls synaptic and cognitive
function in Alzheimer’s models. Nat Neurosci 2016;19:443–53.
[184] Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong C-X. O-GlcNAcy-
lation regulates phosphorylation of tau: a mechanism involved in
Alzheimer’s disease. Proc Natl Acad Sci U S A 2004;101:10804–9.
[185] Dickey CA, Koren J, Zhang Y-J, Xu Y-F, Jinwal UK, Birnbaum MJ,
et al. Akt and CHIP coregulate tau degradation through coordinated
interactions. Proc Natl Acad Sci U S A 2008;105:3622–7.
[186] Ross CA, Poirier MA. Protein aggregation and neurodegenerative
disease. Nat Med 2004;10 Suppl:S10–7.
[187] Ben Yehuda A, Risheq M, Novoplansky O, Bersuker K, Kopito RR,
Goldberg M, et al. Ubiquitin accumulation on disease associated pro-
tein aggregates is correlated with nuclear ubiquitin depletion, histone
de-ubiquitination and impaired DNA damage response. PLoS One
2017;12:e0169054.
[188] Zhang Y-Q, Sarge KD. Sumoylation of amyloid precursor protein
negatively regulates Abeta aggregate levels. Biochem Biophys Res
Commun 2008;374:673–8.
[189] Rezaei-Ghaleh N, Amininasab M, Kumar S, Walter J,
Zweckstetter M. Phosphorylation modifies the molecular stability
of b-amyloid deposits. Nat Commun 2016;7:11359.
[190] �Simi�c G, Babi�c Leko M, Wray S, Harrington C, Delalle I, Jovanov-
Milo�sevi�c N, et al. Tau Protein hyperphosphorylation and aggrega-
tion in Alzheimer’s disease and other tauopathies, and possible neu-
roprotective strategies. Biomolecules 2016;6:6.
[191] Gorsky MK, Burnouf S, Dols J, Mandelkow E, Partridge L. Acetyla-
tion mimic of lysine 280 exacerbates human Tau neurotoxicity
in vivo. Sci Rep 2016;6:22685.
[192] Barrett PJ, Timothy Greenamyre J. Post-translational modification of
a-synuclein in Parkinson’s disease. Brain Res 2015;1628:247–53.
[193] Duce JA, Wong BX, Durham H, Devedjian J-C, Smith DP, Devos D.
Post translational changes to a-synuclein control iron and dopamine
trafficking; a concept for neuron vulnerability in Parkinson’s disease.
Mol Neurodegener 2017;12:45.
[194] Silva A, de Almeida AV, Macedo-Ribeiro S. Polyglutamine expan-
sion diseases: More than simple repeats. J Struct Biol 2018;
201:139–54.
[195] Saudou F, Humbert S. The biology of huntingtin. Neuron 2016;
89:910–26.
[196] Sargeant DP, Deverasetty S, Strong CL, Alaniz IJ, Bartlett A,
Brandon NR, et al. The HIVToolbox 2 web system integrates
sequence, structure, function and mutation analysis. PLoS One
2014;9:e98810.
� 25 July 2018 � 9:16 am � ce
2119
S. Sharma et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19 17
2120
2121
2122
2123
2124
2125
2126
2127
2128
2129
2130
2131
2132
2133
2134
2135
2136
2137
2138
2139
2140
2141
2142
2143
2144
2145
2146
2147
2148
2149
2150
2151
2152
2153
2154
2155
2156
2157
2158
2159
2160
2161
2162
2163
2164
2165
2166
2167
2168
2169
2170
2171
2172
2173
2174
2175
2176
2177
2178
2179
2180
2181
2182
2183
2184
2185
2186
2187
2188
2189
2190
2191
2192
2193
2194
2195
2196
2197
2198
2199
2200
2201
2202
2203
2204
2205
2206
2207
2208
2209
2210
2211
2212
2213
2214
2215
2216
2217
2218
2219
2220
2221
2222
2223
2224
2225
2226
2227
2228
2229
2230
2231
2232
2233
2234
2235
2236
2237
2238
2239
2240
2241
2242
2243
2244
2245
2246
2247
2248
2249
2250
2251
2252
[197] Sarmady M, Dampier W, Tozeren A. Sequence- and interactome-
based prediction of viral protein hotspots targeting host proteins: a
case study for HIV Nef. PLoS One 2011;6:e20735.
[198] Xue B, Brown CJ, Dunker AK, Uversky VN. Intrinsically disordered
regions of p53 family are highly diversified in evolution. Biochim
Biophys Acta 2013;1834:725–38.
[199] Fernandez-Fernandez MR, Sot B. The relevance of protein-protein
interactions for p53 function: the CPE contribution. Protein Eng
Des Sel 2011;24:41–51.
[200] Visscher PM,WrayNR, ZhangQ, Sklar P,McCarthyMI, BrownMA,
et al. 10 Years of GWAS discovery: biology, function, and translation.
Am J Hum Genet 2017;101:5–22.
[201] Singleton A, Hardy J. The evolution of genetics: Alzheimer’s and
Parkinson’s diseases. Neuron 2016;90:1154–63.
[202] Guerreiro RJ, Gustafson DR, Hardy J. The genetic architecture of
Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiol Ag-
ing 2012;33:437–56.
[203] Gatz M, Pedersen NL, Berg S, Johansson B, Johansson K,
Mortimer JA, et al. Heritability for Alzheimer’s disease: the study
of dementia in Swedish twins. J Gerontol A Biol Sci Med Sci
1997;52:M117–25.
[204] Nicolas G, Charbonnier C, Campion D. From common to rare vari-
ants: the genetic component of Alzheimer disease. Hum Hered
2016;81:129–41.
[205] Rovelet-LecruxA, HannequinD, Raux G, LeMeur N, Laquerri�ere A,
Vital A, et al. APP locus duplication causes autosomal dominant
early-onset Alzheimer disease with cerebral amyloid angiopathy.
Nat Genet 2006;38:24–6.
[206] Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D,
Wauters J, et al. APP duplication is sufficient to cause early onset
Alzheimer’s dementia with cerebral amyloid angiopathy. Brain
2006;129:2977–83.
[207] Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, et al.
Genome-wide association study identifies four novel loci associated
with Alzheimer’s endophenotypes and disease modifiers. Acta Neu-
ropathol 2017;133:839–56.
[208] Guo Q, Wang Z, Li H, Wiese M, Zheng H. APP physiological and
pathophysiological functions: insights from animal models. Cell
Res 2012;22:78–89.
[209] Corti O, Lesage S, Brice A. What genetics tells us about the causes
and mechanisms of Parkinson’s disease. Physiol Rev 2011;
91:1161–218.
[210] Verstraeten A, Theuns J, Van Broeckhoven C. Progress in unraveling
the genetic etiology of Parkinson disease in a genomic era. Trends
Genet 2015;31:140–9.
[211] Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s dis-
ease. N Engl J Med 2003;348:1356–64.
[212] Hardy J. Genetic analysis of pathways to Parkinson disease. Neuron
2010;68:201–6.
[213] Chang D, Nalls MA, Hallgr�ımsd�ottir IB, Hunkapiller J, van der
Brug M, Cai F, et al. A meta-analysis of genome-wide association
studies identifies 17 new Parkinson’s disease risk loci. Nat Genet
2017;49:1511–6.
[214] Doggett EA, Zhao J,Mork CN, HuD, Nichols RJ. Phosphorylation of
LRRK2 serines 955 and 973 is disrupted by Parkinson’s disease mu-
tations and LRRK2 pharmacological inhibition. J Neurochem 2012;
120:37–45.
[215] Javed H, KamalMA, Ojha S. An overview on the role of a -synuclein
in experimental models of Parkinson’s disease from pathogenesis to
therapeutics. CNS Neurol Disord Drug Targets 2016;15:1240–52.
[216] Tremblay M-�E, Lowery RL, Majewska AK. Microglial interactions
with synapses are modulated by visual experience. PLoS Biol
2010;8:e1000527.
[217] Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B. Microglia: dy-
namic mediators of synapse development and plasticity. Trends Im-
munol 2015;36:605–13.
FLA 5.5.0 DTD � TRCI168_proof
[218] Lambert J-C, Heath S, Even G, Campion D, Sleegers K, Hiltunen M,
et al. Genome-wide association study identifies variants at CLU and
CR1 associated with Alzheimer’s disease. Nat Genet 2009;
41:1094–9.
[219] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R,
Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies
11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013;
45:1452–8.
[220] Hollingworth P, Harold D, Sims R, Gerrish A, Lambert J-C,
Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/
MS4A4E, EPHA1, CD33 and CD2AP are associated with Alz-
heimer’s disease. Nat Genet 2011;43:429–35.
[221] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E,
Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl
J Med 2013;368:117–27.
[222] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE,
Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4
allele and the risk of Alzheimer’s disease in late onset families. Sci-
ence 1993;261:921–3.
[223] DeMattos RB, Cirrito JR, Parsadanian M, May PC, O’Dell MA,
Taylor JW, et al. ApoE and clusterin cooperatively suppress Abeta
levels and deposition: evidence that ApoE regulates extracellular
Abeta metabolism in vivo. Neuron 2004;41:193–202.
[224] Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN,
Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits micro-
glial uptake of amyloid beta. Neuron 2013;78:631–43.
[225] Satoh K, Abe-Dohmae S, Yokoyama S, St George-Hyslop P,
Fraser PE. ATP-binding cassette transporter A7 (ABCA7) loss of
function alters Alzheimer amyloid processing. J Biol Chem 2015;
290:24152–65.
[226] Sakae N, Liu C-C, ShinoharaM, Frisch-Daiello J, Ma L, Yamazaki Y,
et al. ABCA7 deficiency accelerates amyloid-b generation and Alz-
heimer’s neuronal pathology. J Neurosci 2016;36:3848–59.
[227] Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y,
Gilfillan S, et al. TREM2 sustains microglial expansion during
aging and response to demyelination. J Clin Invest 2015;
125:2161–70.
[228] Ulrich JD, Holtzman DM. TREM2 function in Alzheimer’s disease
and neurodegeneration. ACS Chem Neurosci 2016;7:420–7.
[229] Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G,
et al. TREM2 deficiency exacerbates tau pathology through dysregu-
lated kinase signaling in a mouse model of tauopathy. Mol Neurode-
gener 2017;12:74.
[230] Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE,
Ransohoff RM, et al. Disease progression-dependent effects of
TREM2 deficiency in a mouse model of Alzheimer’s disease. J Neu-
rosci 2017;37:637–47.
[231] Lyon KF, Strong CL, Schooler SG, Young RJ, Roy N, Ozar B, et al.
Natural variability of minimotifs in 1092 people indicates that mini-
motifs are targets of evolution. Nucleic Acids Res 2015;
43:6399–412.
[232] Roubroeks JAY, Smith RG, van den Hove DLA, Lunnon K. Epige-
netics and DNA methylomic profiling in Alzheimer’s disease and
other neurodegenerative diseases. J Neurochem 2017;143:158–70.
[233] Hwang J-Y, Aromolaran KA, Zukin RS. The emerging field of epige-
netics in neurodegeneration and neuroprotection. Nat Rev Neurosci
2017;18:347–61.
[234] Allis CD, Jenuwein T. Themolecular hallmarks of epigenetic control.
Nat Rev Genet 2016;17:487–500.
[235] Jimenez-Pacheco A, Franco JM, Lopez S, Gomez-Zumaquero JM,
Magdalena Leal-Lasarte M, Caballero-Hernandez DE, et al. Epige-
netic mechanisms of gene regulation in amyotrophic lateral sclerosis.
Adv Exp Med Biol 2017;978:255–75.
[236] Francelle L, Lotz C, Outeiro T, Brouillet E,Merienne K. Contribution
of neuroepigenetics to Huntington’s disease. Front Hum Neurosci
2017;11:17.
� 25 July 2018 � 9:16 am � ce
2253
23
S. Sharma et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-1918
2254
2255
2256
2257
2258
2259
2260
2261
2262
2263
2264
2265
2266
2267
2268
2269
2270
2271
2272
2273
2274
2275
2276
2277
2278
2279
2280
2281
2282
2283
2284
2285
2286
2287
2288
2289
2290
2291
2292
2293
2294
2295
2296
2297
2298
2299
2300
2301
2302
2303
2304
2305
2306
2307
2308
2309
2310
2311
2312
2313
2314
2315
2316
2317
2318
2319
2320
2321
2322
2323
2324
2325
2326
2327
2328
2329
2330
2331
2332
2333
2334
2335
2336
2337
2338
2339
2340
2341
2342
2343
2344
2345
2346
2347
2348
2349
2350
2351
2352
2353
2354
2355
2356
2357
2358
2359
2360
2361
2362
2363
2364
2365
2366
2367
2368
2369
2370
2371
2372
2373
2374
2375
2376
2377
2378
2379
2380
2381
2382
2383
2384
2385
2386
[237] Bassi S, Tripathi T, Monziani A, Di Leva F, Biagioli M. Epigenetics
of Huntington’s disease. Adv Exp Med Biol 2017;978:277–99.
[238] Narayan P, DragunowM. Alzheimer’s disease and histone code alter-
ations. Adv Exp Med Biol 2017;978:321–36.
[239] Pavlou MAS, Outeiro TF. Epigenetics in Parkinson’s disease. Adv
Exp Med Biol 2017;978:363–90.
[240] Liu H, Tang T-S, Guo C. Epigenetic profiles in polyglutamine disor-
ders. Epigenomics 2018;10:9–25.
[241] Usmani SS, Bedi G, Samuel JS, Singh S, Kalra S, Kumar P, et al.
THPdb: Database of FDA-approved peptide and protein therapeutics.
PLoS One 2017;12:e0181748.
[242] Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molec-
ular interplay between mammalian target of rapamycin (mTOR),
amyloid-beta, and Tau: effects on cognitive impairments. J Biol
Chem 2010;285:13107–20.
[243] Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O,
Bredesen D, et al. Inhibition of mTOR by rapamycin abolishes cogni-
tive deficits and reduces amyloid-beta levels in a mouse model of
Alzheimer’s disease. PLoS One 2010;5:e9979.
[244] Rodriguez-Navarro JA, Cuervo AM. Autophagy and lipids: tight-
ening the knot. Semin Immunopathol 2010;32:343–53.
[245] Heiseke A, Aguib Y, Riemer C, Baier M, Sch€atzl HM. Lithium in-
duces clearance of protease resistant prion protein in prion-infected
cells by induction of autophagy. J Neurochem 2009;109:25–34.
[246] Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC.
Alpha-Synuclein is degraded by both autophagy and the proteasome.
J Biol Chem 2003;278:25009–13.
[247] Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins
with polyglutamine and polyalanine expansions are degraded by
autophagy. Hum Mol Genet 2002;11:1107–17.
[248] Skovronsky DM, Lee VM-Y, Trojanowski JQ. Neurodegenerative
diseases: new concepts of pathogenesis and their therapeutic implica-
tions. Annu Rev Pathol 2006;1:151–70.
[249] Rachakonda V, Pan TH, Le WD. Biomarkers of neurodegenerative
disorders: how good are they? Cell Res 2004;14:347–58.
[250] MacLeod R, Hillert E-K, Cameron RT, Baillie GS. The role and ther-
apeutic targeting of a-, b- and g-secretase in Alzheimer’s disease.
Future Sci OA 2015;1:FSO11.
[251] Evers MM, Toonen LJA, van Roon-MomWMC. Antisense oligonu-
cleotides in therapy for neurodegenerative disorders. Adv Drug Deliv
Rev 2015;87:90–103.
[252] Magen I, Hornstein E. Oligonucleotide-based therapy for neurode-
generative diseases. Brain Res 2014;1584:116–28.
[253] Gong B, Radulovic M, Figueiredo-Pereira ME, Cardozo C. The
ubiquitin-proteasome system: potential therapeutic targets for Alz-
heimer’s disease and spinal cord injury. Front Mol Neurosci 2016;
9:4.
[254] El-Agnaf OMA, Paleologou KE, Greer B, Abogrein AM, King JE,
Salem SA, et al. A strategy for designing inhibitors of alpha-
synuclein aggregation and toxicity as a novel treatment for Parkin-
son’s disease and related disorders. FASEB J 2004;18:1315–7.
[255] Schlessinger J, Lemmon MA. SH2 and PTB domains in tyrosine ki-
nase signaling. Sci STKE 2003;2003:RE12.
[256] Dev KK. Making protein interactions druggable: targeting PDZ do-
mains. Nat Rev Drug Discov 2004;3:1047–56.
[257] Abou-Abbass H, Abou-El-HassanH, BahmadH, Zibara K, Zebian A,
Youssef R, et al. Glycosylation and other PTMs alterations in neuro-
degenerative diseases: Current status and future role in neurotrauma.
Electrophoresis 2016;37:1549–61.
[258] Hawkes CA, Ng V, McLaurin J. Small molecule inhibitors of Ab-ag-
gregation and neurotoxicity. Drug Dev Res 2009;70:111–24.
[259] Heerboth S, Lapinska K, Snyder N, Leary M, Rollinson S, Sarkar S.
Use of epigenetic drugs in disease: an overview. Genet Epigenet
2014;6:9–19.
[260] Lewis S. Neurodegenerative disease: Restoring balance. Nat Rev
Neurosci 2016;17:400.
FLA 5.5.0 DTD � TRCI168_proof
[261] Bray N. Neurodegenerative disease: Losing the way. Nat Rev Neuro-
sci 2017;18:129.
[262] Krumova P, Weishaupt JH. Sumoylation in neurodegenerative dis-
eases. Cell Mol Life Sci 2013;70:2123–38.
[263] Oddo S. The ubiquitin-proteasome system in Alzheimer’s disease. J
Cell Mol Med 2008;12:363–73.
[264] D’Alton S, Lewis J. Therapeutic and diagnostic challenges for fron-
totemporal dementia. Front Aging Neurosci 2014;6:204.
[265] Sporns O, Chialvo DR, Kaiser M, Hilgetag CC. Organization, devel-
opment and function of complex brain networks. Trends Cogn Sci
2004;8:418–25.
[266] Zhang Q, Ma C, Gearing M, Wang PG, Chin L-S, Li L. Integrated
proteomics and network analysis identifies protein hubs and network
alterations in Alzheimer’s disease. Acta Neuropathol Commun 2018;
6:19.
[267] Crucitti P, Latora V, Marchiori M. Model for cascading failures in
complex networks. Phys Rev E Stat Nonlin Soft Matter Phys 2004;
69:045104.
[268] Turau V, Weyer C. Cascading failures caused by node overloading in
complex networks. IEEE 2016:1–6. Q
[269] Jones DT, Knopman DS, Gunter JL, Graff-Radford J, Vemuri P,
Boeve BF, et al. Cascading network failure across the Alzheimer’s
disease spectrum. Brain 2016;139:547–62.
[270] Jones DT, Graff-Radford J, Lowe VJ, Wiste HJ, Gunter JL,
SenjemML, et al. Tau, amyloid, and cascading network failure across
the Alzheimer’s disease spectrum. Cortex 2017;97:143–59.
[271] Gao H-M, Hong J-S. Why neurodegenerative diseases are progres-
sive: uncontrolled inflammation drives disease progression. Trends
Immunol 2008;29:357–65.
[272] Li Y, TanM-S, Jiang T, Tan L.Microglia in Alzheimer’s disease. Bio-
med Res Int 2014;2014:437483.
[273] Van Roey K, Gibson TJ, Davey NE.Motif switches: decision-making
in cell regulation. Curr Opin Struct Biol 2012;22:378–85.
[274] Alonso Vilatela ME, L�opez-L�opez M, Yescas-G�omez P. Genetics of
Alzheimer’s disease. Arch Med Res 2012;43:622–31.
[275] Thomas SN, Funk KE, Wan Y, Liao Z, Davies P, Kuret J, et al. Dual
modification of Alzheimer’s disease PHF-tau protein by lysine
methylation and ubiquitylation: a mass spectrometry approach.
Acta Neuropathol 2012;123:105–17.
[276] Bhattacharyya R, Barren C, Kovacs DM. Palmitoylation of amyloid
precursor protein regulates amyloidogenic processing in lipid rafts. J
Neurosci 2013;33:11169–83.
[277] Sacksteder CA, Qian W-J, Knyushko TV, Wang H, Chin MH,
Lacan G, et al. Endogenously nitrated proteins in mouse brain: links
to neurodegenerative disease. Biochemistry 2006;45:8009–22.
[278] Blokhuis AM, Groen EJN, Koppers M, van den Berg LH,
Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis.
Acta Neuropathol 2013;125:777–94.
[279] Lee S, Kim H-J. Prion-like mechanism in amyotrophic lateral scle-
rosis: are protein aggregates the key? Exp Neurobiol 2015;24:1–7.
[280] Furukawa Y, Kaneko K, Yamanaka K, O’Halloran TV, Nukina N.
Complete loss of post-translational modifications triggers fibrillar ag-
gregation of SOD1 in the familial form of amyotrophic lateral scle-
rosis. J Biol Chem 2008;283:24167–76.
[281] Valle C, Carr�ı MT. Cysteine modifications in the pathogenesis of
ALS. Front Mol Neurosci 2017;10:5.
[282] Freixes M, Puig B, Rodr�ıguez A, Torrej�on-Escribano B, Blanco R,
Ferrer I. Clusterin solubility and aggregation in Creutzfeldt-Jakob
disease. Acta Neuropathol 2004;108:295–301.
[283] Ermonval M, Mouillet-Richard S, Codogno P, Kellermann O, Botti J.
Evolving views in prion glycosylation: functional and pathological
implications. Biochimie 2003;85:33–45.
[284] Kaneko K, Vey M, Scott M, Pilkuhn S, Cohen FE, Prusiner SB.
COOH-terminal sequence of the cellular prion protein directs subcel-
lular trafficking and controls conversion into the scrapie isoform.
Proc Natl Acad Sci U S A 1997;94:2333–8.
� 25 July 2018 � 9:16 am � ce
2387
26
S. Sharma et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19 19
2388
2389
2390
2391
2392
2393
2394
2395
2396
2397
2398
2399
2400
2401
2402
2403
2404
2405
2406
2407
2408
2409
2410
2411
2412
2413
2414
2415
2416
2417
2418
2419
2420
2421
2422
2423
2424
2425
2426
2427
2428
2429
2430
2431
2432
2433
2434
2435
2436
2437
2438
2439
2440
2441
2442
2443
2444
2445
2446
2447
2448
2449
2450
2451
2452
2453
2454
2455
2456
2457
2458
2459
2460
2461
2462
2463
2464
2465
2466
2467
2468
2469
2470
2471
2472
2473
2474
2475
2476
2477
2478
2479
2480
2481
2482
2483
[285] Gass CS, Luis CA, Meyers TL, Kuljis RO. Familial Creutzfeldt-
Jakob disease: a neuropsychological case study. Arch Clin Neuropsy-
chol 2000;15:165–75.
[286] Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and famil-
ial CJD: classification and characterisation. Br Med Bull 2003;
66:213–39.
[287] Arrasate M, Finkbeiner S. Protein aggregates in Huntington’s dis-
ease. Exp Neurol 2012;238:1–11.
[288] Kumar KR, Weissbach A, HeldmannM, Kasten M, Tunc S, Sue CM,
et al. Frequency of the D620N mutation in VPS35 in Parkinson dis-
ease. Arch Neurol 2012;69:1360–4.
[289] Zimprich A, Benet-Pag�es A, Struhal W, Graf E, Eck SH, Offman MN,
et al. Amutation inVPS35, encoding a subunit of the retromer complex,
causes late-onset Parkinson disease.Am JHumGenet 2011;89:168–75.
[290] Vilari~no-G€uell C, Wider C, Ross OA, Dachsel JC, Kachergus JM,
Lincoln SJ, et al. VPS35 mutations in Parkinson disease. Am J
Hum Genet 2011;89:162–7.
[291] Wang W, Ma X, Zhou L, Liu J, Zhu X. A conserved retromer sorting
motif is essential for mitochondrial DLP1 recycling by VPS35 in Par-
kinson’s disease model. Hum Mol Genet 2017;26:781–9.
[292] Chartier-Harlin M-C, Dachsel JC, Vilari~no-G€uell C, Lincoln SJ,
Lepretre F, HulihanMM, et al. Translation initiator EIF4G1mutations
in familial Parkinson disease. Am J Hum Genet 2011;89:398–406.
[293] Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D.
Impaired degradation of mutant alpha-synuclein by chaperone-
mediated autophagy. Science 2004;305:1292–5.
[294] Vilari~no-G€uell C, Rajput A, Milnerwood AJ, Shah B, Szu-Tu C,
Trinh J, et al. DNAJC13 mutations in Parkinson disease. Hum Mol
Genet 2014;23:1794–801.
FLA 5.5.0 DTD � TRCI168_proof
[295] Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease.
J Geriatr Psychiatry Neurol 2010;23:228–42.
[296] Merry DE, Kobayashi Y, Bailey CK, Taye AA, Fischbeck KH. Cleav-
age, aggregation and toxicity of the expanded androgen receptor in
spinal and bulbar muscular atrophy. Hum Mol Genet 1998;
7:693–701.
[297] Panet-Raymond V, Gottlieb B, Beitel LK, Schipper H, Timiansky M,
Pinsky L, et al. Characterization of intracellular aggregates using
fluorescently-tagged polyglutamine-expanded androgen receptor.
Neurotox Res 2001;3:259–75.
[298] Berger TR Q, Montie HL, Jain P, Legleiter J, Merry DE. Identifi-
cation of novel polyglutamine-expanded aggregation species in
spinal and bulbar muscular atrophy. Brain Res 2015;1628:
254–64.
[299] Miller N, Feng Z, Edens BM, Yang B, Shi H, Sze CC, et al. Non-
aggregating tau phosphorylation by cyclin-dependent kinase 5 con-
tributes to motor neuron degeneration in spinal muscular atrophy. J
Neurosci 2015;35:6038–50.
[300] Mark MD, Krause M, Boele H-J, Kruse W, Pollok S, Kuner T,
et al. Spinocerebellar ataxia type 6 protein aggregates cause def-
icits in motor learning and cerebellar plasticity. J Neurosci 2015;
35:8882–95.
[301] Seki T, Shimahara T, Yamamoto K, Abe N, Amano T, Adachi N, et al.
Mutant gammaPKC found in spinocerebellar ataxia type 14 induces
aggregate-independent maldevelopment of dendrites in primary
cultured Purkinje cells. Neurobiol Dis 2009;33:260–73.
[302] Chen F, David D, Ferrari A, G€otz J. Posttranslational modifications of
tau–role in human tauopathies and modeling in transgenic animals.
Curr Drug Targets 2004;5:503–15.
� 25 July 2018 � 9:16 am � ce
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