from mechanisms of memory, second edition by j. david sweatt, ph.d. chapter 11: inherited disorders...
TRANSCRIPT
From Mechanisms of Memory, second editionBy J. David Sweatt, Ph.D.
Chapter 11:Inherited Disorders of Human Memory – Mental Retardation
Syndromes
Chapter 11: Mental Retardation Syndromes
Table I: Mouse Models of Human Mental Retardation Syndromes
Human Mental Retardation Syndromes
Gene Product Potential Targets
Mouse Model
ReferencesLearning Defects?
LTP Change?
Neurofibromatosis Neurofibromin 1 (NF1) ras/ ERK + + Costa et al (4, 39)
adenylyl cyclase Tong et al (9)
cytoskeleton
Coffin-Lowry Ribosomal S6 Kinase2 CREB + ? Dufresne et al (12)
Syndrome (rsk2) ribosomal S6 protein Harum et al (13)
Angelman Syndrome
Ubiquitin Ligase (E6AP) p53 tumor suppressor + + Jiang et al (40)
protein, others?
Fragile X Mental FMR1 Protein (RNA protein synthesis + ?
Bardoni et al (17)
Retardation 1 binding proteins) machinery, (strain
mRNA targeting,dependen
t)
spine structure, LTD
Fragile X Mental FMR2 protein Unknown-- + + Gu et al (41)
Retardation 2 (putative transcription Gene Expression
factor)
Rett Syndrome Methyl-CpG Binding Transcriptional ? ?Shahbazian et al (23)
Protein 2 (MeCP2) repressors--regulation
of unknown genes
Myotonic Dystrophy Dystrophin Protein Na+ channels, ? ? Mistry et al (42)
Kinase (DMPK) Tau, many others
Table I: Mouse Models of Human Mental Retardation Syndromes
Continued
Myotonic Dystrophy Dystrophin Protein Na+ channels, ? ? Mistry et al (42)
Kinase (DMPK) Tau, many others
Down Syndrome DS critical locus Multiple genes including + + Siarey et al (36)
(Trisomy 21) DYRK1A and SOD
DYRK1A (minibrain unknown + ? Altafaj et al (35)
kinase homolog)
Superoxide Dismutase Superoxide dependent + + Gahtan et al (43)
(SOD) processes--redox
regulation of PKC, ras,
transcription factors
Williams Syndrome WS critical locus: cytoskeleton + + Morris et al (44)
LIMK-1 extracellular matrix
Elastin spine morphology
Syntaxin 1A
FKBP6
EIFH4
Table I: Mouse Models of Human Mental Retardation Syndromes Cont.
Figure 1
Signaling Pathways Implicated in Human Memory Formation
Figure 2
G Protein
ERK1/2
MEK1/2
Raf1
R1Grb
SOSRas
PKC
R2
B-Raf
PKA
R3
Rap
AC
Gene Expression
Mnk1/2
eIF4E
Protein Synthesis
MAPs
Spine Structure
CRECREB
P
CBP
RSK2
GEF
NF1GAP
Neurofibromatosis MR
NO.
Ca2+
NF1
Ca2+
Nucleus
R4
Coffin-Lowry Syndrome
Rubinstein-TaybiSyndrome
Fragile X Syndrome
Signal Transduction Pathways Involved in Learning and Memory
Fig
ure
3
K-ras
N-ras
Farnesyl Transferase Inhibitor
Ras-Dependent spacial learning deficits in NF1
Figure 4
Ras-Dependent LTP deficits in NF1
Figure 5
E 1
E 1E 1
UbUb
ATP
E2L i g a s eUb
E3Lig as e
Targe tPro te in
E 2Ub
E 3 Targe tPro te in
Ub
Ub Ub
UbUb
Ub
Step 1
Step 2
Complex Formation
Step 3
Step 4
Step 5
E1 Charging
E2 Charging
E2—E3 Transfer
TargetPoly-
Ubiquitination
Ubiquitination Pathway of Proteins
Figure 6
Selective Deficit in Context-Dependent Fear Conditioning in Ube3a Maternal Deficient Mice
Figure 7
Impairment of Hippocampal LTP in Ube3a Maternal Deficient mice
Figure 8
Current Model of Fragile X Mental RetardationCoding Region
Regulatory Region
CGG Expansion in Regulatory Region
Point Mutation in Coding Region
DisruptionOf FMR1 Gene
Loss ofFMR1 Protein (FMRP)
FMR1/FXRInteraction domain
RibosomeInteraction
Domain
RGG BoxKHDomain
KHDomain
RGG Box = Arginine & Glycine-rich domainKH domain = Ribonucleoprotein K homology domain
FMRP = 63K RNA binding protein that binds to poly (G) and poly (U) structures
FMR1 GeneGeneStructure
FMRPStructure
Fragile X Mental Retardation Syndrome
Figure 9
DHPG Induces Greater LTD of Synaptic Responses in Hippocampus
Figure 10
Role of mGluR5 in Fragile X Mental Retardation
Figure 11
A
-20 -10 0 10 20 30 40 50 60
50
100
150
200
250
Mutant
Wildtype
Time (min)
Slo
pe
fE
PS
P
(Sta
nd
ard
ize
d t
o B
as
eli
ne
)
Enhanced LTP in FMR2 Knockout Mice
rho
PAK, ROCK
LIMK-1(Williams Syndrome)
Actin Depolymerization Factor (ADF) / cofilin
Actin Cytoskeleton—Loss of LIMK-1causes increased actin turnover
Altered Dendritic Spine
Augmented LTP, Learning Impairments
rac PKC
Direct phosphorylation(inhibitory)
ADF / Cofilin promotesActin depolymerization
Blue Box 3
Williams Syndrome
Rho
PAK3 (p21 Activated Kinase)
JNK p38
Cytoskeletonraf-1LTD disruption?
Dbl (Diffuse B-cell Lymphoma)Rho GEF6
Rho GAPRho GDI
GEFs+ _
Blue Box 4
Non-Syndromic X-Linked Mental Retardation