BY OUR PLATFORMS
BY THERAPEUTIC AREA
BY RESEARCH STAGE
01 March 2019
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
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.
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