Objective: Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. Methods: We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. Results: We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. Interpretation: This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.

Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy

VANNI, NICOLA AUGUSTO;FRUSCIONE, FLORIANA;STRIANO, PASQUALE;FALACE, ANTONIO;FASSIO, ANNA;MINETTI, CARLO;ZARA, FEDERICO
2014-01-01

Abstract

Objective: Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. Methods: We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. Results: We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. Interpretation: This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/769794
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