ArticleThe Journal of clinical investigation2022
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 57 citations in OpenAlex.
- Deletion of exon 2 in ALS-linkedLife science alliance · 2026Article
- Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.JCI insight · 2026Article
- Characterization of novel and recurrentJournal of neuromuscular diseases · 2026Article
- Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy.The Journal of clinical investigation · 2026Article
- The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion.bioRxiv : the preprint server for biology · 2026Article
- Allele-specific antisense oligonucleotide treatment rescuesbioRxiv : the preprint server for biology · 2026Article
- Modeling lipid homeostasis using stable isotope tracing and flux analysis.Cell metabolism · 2026Article
- Tailoring treatments: pharmacogenomics in the management of neurodegenerative diseases.Acta neurologica Belgica · 2026Review
- Blood 1-Deoxysphingolipid Levels Are Associated With Epidermal Denervation in Small Fiber Neuropathy.Journal of the peripheral nervous system : JPNS · 2025Article
- Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.Nature communications · 2025Article
- Article
- Ceramides in cardiovascular disease: emerging role as independent risk predictors and novel therapeutic targets.Cardiovascular research · 2025Review
- The landscape of renal protein S-acylation in mice with lipid-induced nephrotoxicity.Scientific reports · 2025Article
- ER stress in D1-MSNs mediates cocaine-induced behavioral plasticityFrontiers in pharmacology · 2025Article
- Human genetic defects of sphingolipid synthesis.Journal of inherited metabolic disease · 2025Review
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
- The conformational plasticity of structurally unrelated lipid transport proteins correlates with their mode of action.PLoS biology · 2024Article
- Functional and Molecular Characterization of NewGenes · 2024Article
- SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.Annals of clinical and translational neurology · 2024Article
- RecurrentJournal of neurology, neurosurgery, and psychiatry · 2024Article
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS-expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.
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