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.
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.
Authors: Stefka D Spassieva; Xiaojie Ji; Ye Liu; Kenneth Gable; Jacek Bielawski; Teresa M Dunn; Erhard Bieberich; Lihong Zhao Journal: Proc Natl Acad Sci U S A Date: 2016-05-09 Impact factor: 11.205
Authors: Carolina Courage; Karen L Oliver; Eon Joo Park; Jillian M Cameron; Kariona A Grabińska; Mikko Muona; Laura Canafoglia; Antonio Gambardella; Edith Said; Zaid Afawi; Betul Baykan; Christian Brandt; Carlo di Bonaventura; Hui Bein Chew; Chiara Criscuolo; Leanne M Dibbens; Barbara Castellotti; Patrizia Riguzzi; Angelo Labate; Alessandro Filla; Anna T Giallonardo; Geza Berecki; Christopher B Jackson; Tarja Joensuu; John A Damiano; Sara Kivity; Amos Korczyn; Aarno Palotie; Pasquale Striano; Davide Uccellini; Loretta Giuliano; Eva Andermann; Ingrid E Scheffer; Roberto Michelucci; Melanie Bahlo; Silvana Franceschetti; William C Sessa; Samuel F Berkovic; Anna-Elina Lehesjoki Journal: Am J Hum Genet Date: 2021-04-01 Impact factor: 11.025
Authors: Jakub Sikora; Shaalee Dworski; E Ellen Jones; Mustafa A Kamani; Matthew C Micsenyi; Tomo Sawada; Pauline Le Faouder; Justine Bertrand-Michel; Aude Dupuy; Christopher K Dunn; Ingrid Cong Yang Xuan; Josefina Casas; Gemma Fabrias; David R Hampson; Thierry Levade; Richard R Drake; Jeffrey A Medin; Steven U Walkley Journal: Am J Pathol Date: 2017-04 Impact factor: 4.307