COMMENTARY

Ceramide Center Stage in ProgressiveMyoclonus Epilepsies

Progressive myoclonus epilepsies (PMEs) embody syn-dromes exhibiting myoclonic/tonic–clonic seizures,

progressive ataxia, and dementia. They are uncommonand include sialidosis, Unverricht–Lundborg disease,Lafora disease, the neuronal ceroid lipofuscinoses (NCLs),and myoclonus epilepsy ragged-red fiber syndrome.Although infrequent, combined biochemical and molecu-lar genetic approaches have clarified their pathobiologymore than most inherited epilepsies of childhood.

Vanni et al1 and Mosbech2 describe 2 novel PMEsthat are caused by defects in ceramide (dihydro)synthase(CerS) 1 and 2, respectively, perfectly illustrating thispoint. CerSs catalyze a key step in de novo ceramide syn-thesis, the hub of sphingolipid metabolism (Fig 1).

The term sphingo- was devised by Thudichum3 asthe inscrutable nature of sphingolipids4 evoked the riddleof the sphinx. Galactosylceramide/cerebroside/sphingo-sine/ceramide and sphingomyelin, components of myelin

FIGURE 1: De novo ceramide synthesis pathway defects. N-acylation of a sphingoid base with fatty acids of varying chain lengthand saturation spawns different ceramide species. The process begins by condensation of L-serine and palmitoyl-coenzyme A bythe enzyme serine palmitoyltransferase (SPT) to D-3-ketosphinganine followed by a series of enzymatic steps. A defect in the SPTsubunit 1 protein (SPTLC1) affects the first committed step in de novo ceramide synthesis causing hereditary sensory neuropathytype 1 (HSN1). Defects in GM3 synthase cause an infantile epilepsy syndrome. The generation of dihydroceramides by the (dihy-dro)ceramide synthases CerS1–6 has emerged as a stage for the formation of species-specific dihydroceramides and ceramides.Abnormalities in CLN5, CLN8, CerS1, and CerS2 proteins all result in progressive myoclonus encephalopathies (PMEs) with dimin-ished amounts of C16, C18 or C18:1, and C24 or C24:1 ceramide and dihydroceramide species. NADPH 5 nicotinamide adeninedinucleotide phosphate. [Color figure can be viewed in the online issue, which is available at www.annalsofneurology.org.]

162 VC 2014 American Neurological Association

and cortex, were isolated from human brain by Thudi-chum.3 He is justly called the father of sphingolipidresearch. Cerebrosides,5 sulfatide,6 and gangliosides7 werealso derived from gray and white matter and are impor-tant brain constituents.8

Monogenic defects in degradative pathways of sphin-golipids/glycosphingolipids/phospholipids are ensconced inour psyche. They lead to Tay–Sachs disease/GM2-ganglio-sidosis/GM1-gangliosidosis/Gaucher disease/Krabbe disease/metachromatic leukodystrophy/Niemann–Pick disease Aand B and Farber disease.9,10

Defects in sphingolipid synthetic processes are rarer.Diminished GM3 synthase activity results in an infantileepilepsy syndrome (see Fig 1).11 Defects in SPTLC1(long-chain base 1 subunit of serine palmitoyltransferase),the enzyme catalyzing the initial step of de novo cer-amide synthesis, cause hereditary sensory neuropathytype 1 (see Fig 1).12

These past 3 decades have witnessed ascendance ofthe second messenger ceramide and its bioactive metabo-lites as key signaling molecules in the regulation of apo-ptosis, cell growth, and cell stress modulation. Unravelingthe cell biology of these compounds is now central toadvances in understanding inflammation, cancer, diabetes,and neurodegeneration.13–16

Dissecting sphingolipid pathways with gene knock-outs, RNA interference studies, and use of inhibitors andactivators of specific enzymes in cell and animal modelshas led to new insights into sphingolipid biology.17 Vali-dation of these concepts comes at the expense of natu-rally occurring genetic diseases.

CLN5/CLN8 disease, 2 NCL variants, are caused bydefects in CLN5/CLN8 proteins (CLN5p, CLN8p).18

These indirectly activate (dihydro)ceramide synthase 1and 2 (CerS1/CerS2; see Fig 1). CerS1–6 synthesizedihydroceramides, precursors of ceramides, and exhibittissue specificity and proclivity for species-specific acyl-CoAs.19 CLN5p and CLN8p activate CerSs generatingC16/C18/C24 ceramides in Cln8 mouse fibroblasts andC16/C24 ceramides/dihydroceramides in CLN5-deficientfibroblasts, respectively.18

Vanni et al1 bring the story full circle by identifyingan actual homozygous CerS1 mutation in siblings withprogressive dementia and myoclonus (see Fig 1). CerS1is abundantly expressed in neurons of neocortex/hippo-campus/cerebellum with specificity for (dihydro)C18 cer-amides, important components of brain gangliosides.The authors elegantly demonstrate links between CerS1defects and upregulation of endoplasmic reticulum (ER)stress markers, substantiating earlier work connectingC18 ceramide, the ER stress response, autophagy, andneurodegeneration in the Cln8 mouse model for CLN8disease.20

Mosbech2 describes a heterozygous deletion in theCerS2 gene that diminishes C24/C26-ceramide/dihydro-ceramides by 50%, causing cognitive decline, tremor, and

progressive myoclonus (see Fig 1). CerS2 is substantiallyexpressed in myelin-producing oligodendrocytes andSchwann cells.

Tight regulation of ceramide species/sphingolipidlevels/CerS activity impacts functioning of the brain.21

NCLs CLN1–6 and CLN8 all manifest disturbed sphin-golipid levels.22–25 Altered ceramide/dihydroceramide lev-els consistent with diminished CerS1/CerS2 activities arenow described in 4 genetically distinct PMEs,1,2,18 mostnotably in the reports by Vanni et al and Mosbech.

Proper functioning of lipid rafts (LRs) depends onstable sphingo-/glycosphingolipid stoichiometries.23,26 LRsorchestrate assembly of membrane protein complexes andsignaling activities. Altered sphingolipid levels and physicaldisruption of LR integrity is evident in CLN1–6/CLN8and notably, CerS2 disease.2,23 Other neurodegenerativediseases with disturbed sphingolipid levels include Parkin-son disease, Alzheimer disease, human immunodeficiencyvirus encephalopathy, Huntington disease, amyotrophiclateral sclerosis, and prion diseases. A biomarker for earlydementia in Alzheimer disease is elevation of ceramide lev-els in cerebrospinal fluid,27 so sphingolipids can serve asbiomarkers for monitoring progression or response toemerging therapies in some neurodegenerative diseases.28

Innovations in lipidomics have generated opportunitiesfor treating neurodegeneration. Examples include developinggalactosylceramide as treatment for CLN3 disease23 or design-ing novel Cers1 and 2 activators, such as fenretinide, to turnon CerSs as a remedy for CerS1 or CerS2 disease.18,29

Potential Conflicts of Interest

patent Application Methods and compositions for treat-ing disorders caused by deficiency in a gene product of aCLN gene. Inventor: Rose-Mary Boustany (AUB andDuke University). Methods and compositions for treatingdisorders caused by deficiency in a gene product of aCLN gene. Inventor: Rose-Mary Boustany (AUB andDuke University). Provisional filing date Jan 1, 2009.US61/113,676.

Rose-Mary Boustany, MD

Departments of Pediatrics, Adolescent Medicine, and Biochemistry and

Molecular Medicine

American University of Beirut Medical Center

Beirut, Lebanon

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Boustany: Ceramide in PMEs

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DOI: 10.1002/ana.24228

ANNALS of Neurology

164 Volume 76, No. 2