Journal article
Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis
Nature medicine, Vol.27(7), pp.1197-1204
07/2021
DOI: 10.1038/s41591-021-01346-1
PMCID: PMC9309980
PMID: 34059824
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.
Details
- Title: Subtitle
- Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis
- Creators
- Payam Mohassel - National Institute of Neurological Disorders and StrokeSandra Donkervoort - National Institute of Neurological Disorders and StrokeMuseer A Lone - University Hospital of ZurichMatthew Nalls - National Institute of Neurological Disorders and StrokeKenneth Gable - Uniformed Services University of the Health SciencesSita D Gupta - Uniformed Services University of the Health SciencesA Reghan Foley - National Institute of Neurological Disorders and StrokeYing Hu - National Institute of Neurological Disorders and StrokeJonas Alex Morales Saute - Universidade Federal do Rio Grande do SulAna Lucila Moreira - Universidade de São PauloFernando Kok - Hospital das Clínicas da Faculdade de Medicina da Universidade de São PauloAlessandro Introna - University of Bari Aldo MoroGiancarlo Logroscino - University of Bari Aldo MoroChristopher Grunseich - National Institute of Neurological Disorders and StrokeAlec R Nickolls - National Institute of Neurological Disorders and StrokeNaemeh Pourshafie - National Institute of Neurological Disorders and StrokeSarah B Neuhaus - National Institute of Neurological Disorders and StrokeDimah Saade - National Institute of Neurological Disorders and StrokeAndrea Gangfuß - University of Duisburg-EssenHeike Kölbel - University of Duisburg-EssenZoe Piccus - Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentClaire E Le Pichon - Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentChiara Fiorillo - University of GenoaCindy V Ly - Washington University in St. LouisAna Töpf - Newcastle UniversityLauren Brady - McMaster UniversitySabine Specht - Newcastle UniversityAliza Zidell - Hackensack University Medical CenterHelio Pedro - Hackensack University Medical CenterEric Mittelmann - Hackensack University Medical CenterFlorian P Thomas - Hackensack University Medical CenterKatherine R Chao - Broad InstituteChamindra G Konersman - University of California San DiegoMegan T Cho - GeneDxTracy Brandt - GeneDxVolker Straub - John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne UKAnne M Connolly - Nationwide Children's HospitalUlrike Schara - University of Duisburg-EssenAndreas Roos - University of Duisburg-EssenMark Tarnopolsky - McMaster UniversityAhmet Höke - Johns Hopkins UniversityRobert H Brown - University of Massachusetts Chan Medical SchoolChia-Hsueh Lee - St. Jude Children's Research HospitalThorsten Hornemann - University Hospital of ZurichTeresa M Dunn - Uniformed Services University of the Health SciencesCarsten G Bönnemann - National Institutes of Health
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.27(7), pp.1197-1204
- DOI
- 10.1038/s41591-021-01346-1
- PMID
- 34059824
- PMCID
- PMC9309980
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Grant note
- R01 NS072446 / NINDS NIH HHS grant # W81XWH-20-1-0219 / United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP) grant #31003A_179371 / Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) K08 NS10762 / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) K08 NS107621 / NINDS NIH HHS
- Language
- English
- Date published
- 07/2021
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984353834902771
Metrics
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