A knockdown approach for disease modeling in zebrafish, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod.
Devesh C Pant 1 2, Imen Dorboz 3, Agatha Schluter 1 2, Stéphane Fourcade 1 2, Nathalie Launay 1 2, Javier Joya 1 2, Sergio Aguilera-Albesa 4, Maria Eugenia Yoldi 4, Carlos Casasnovas 1 2 5, Mary J Willis 6, Montserrat Ruiz 1 2, Dorothée Ville 7, Gaetan Lesca 8, Karine Siquier-Pernet 9 10, Isabelle Desguerre 9 10, Huifang Yan 11 12, Jingmin Wang 11, Margit Burmeister 12 13, Lauren Brady 14, Mark Tarnopolsky 14, Carles Cornet 15, Davide Rubbini 15, Javier Terriente 15, Kiely N James 16, Damir Musaev 16, Maha S Zaki 17, Marc C Patterson 18, Brendan C Lanpher 19, Eric W Klee 19 20, Filippo Pinto E Vairo 19 20, Elizabeth Wohler 21, Nara Lygia de M Sobreira 22, Julie S Cohen 23, Reza Maroofian 24, Hamid Galehdari 25, Neda Mazaheri 25 26, Gholamreza Shariati 26 27, Laurence Colleaux 9 10, Diana Rodriguez 28 29, Joseph G Gleeson 16, Cristina Pujades 30, Ali Fatemi 23 31, Odile Boespflug-Tanguy 3 32, Aurora Pujol 1 2 33
1Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
2Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
3INSERM UMR 1141, DHU PROTECT, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
4Pediatric Neurology Unit, Department of Pediatrics, Navarra Health Service, Navarrabiomed, Pamplona, Spain.
5Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, c/Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
6Department of Pediatrics, Naval Medical Center San Diego, San Diego, California, USA.
7Department of Neuropediatrics, Lyon University Hospital, Lyon, France.
8Department of Medical Genetics, Lyon University Hospital and GENDEV team CNRS UMR 5292, INSERM U1028, CRNL, and University Claude Bernard Lyon 1, Lyon, France.
9Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
10Developmental Brain Disorders Laboratory, INSERM UMR 1163, Paris, France.
11Department of Pediatrics, Peking University First Hospital, Beijing, China.
12Molecular & Behavioral Neuroscience Institute, and.
13Departments of Computational Medicine & Bioinformatics, Psychiatry and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
14Department of Pediatrics (Neuromuscular and Neurometabolics), McMaster Children's Hospital, Hamilton, Ontario, Canada.
15ZeClinics SL, PRBB, Barcelona, Spain.
16Laboratory for Pediatric Brain Disease, Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, California, USA.
17Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
18Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
19Department of Clinical Genomics and.
20Center for Individualized Medicine, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
21McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
22McKusick-Nathans Institute of Genetic Medicine, and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
23Moser Center for Leukodystrophies at the Kennedy Krieger Institute, Baltimore, Maryland, USA.
24Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's, University of London, London, United Kingdom.
25Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
26Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran.
27Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
28APHP, Department of Neuropediatrics, National Reference Center for Neurogenetic Disorders, Hôpital Armand-Trousseau, GHUEP, Paris, France.
29GRC ConCer-LD, Sorbonne Universités, UPMC Université, Paris, France.
30Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
31Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
32Assistance Publique des Hopitaux de Paris (APHP), Reference Center for Leukodystrophies and Rare Leukoencephalopathies (LEUKOFRANCE), Hôpital Robert Debré, Paris, France.
33Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain.
Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.
View full article The Journal of Clinical Investigation