ArticleMovement disorders : official journal of the Movement Disorder Society2019
SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.
Article in Movement disorders : official journal of the Movement Disorder Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers, 1 of them a synthesis that pooled it.
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Who cites it
70 citing papers in PubMed, 1 synthesis or guideline pooled it, 112 citations in OpenAlex.
- GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.Brain : a journal of neurology · 2023Pooled it
- Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.Brain : a journal of neurology · 2026Article
- A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- CRISPR-Based Gene Therapy for Brain Disease.Molecular neurobiology · 2026Review
- Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease.Molecular systems biology · 2026Article
- Prosaposin in CNS health and disease, metabolic stress and exercise adaptation.Journal of molecular medicine (Berlin, Germany) · 2026Review
- Sphingolipid-Neuroinflammation Axis in Parkinson's Disease: Focus on S1P/SPHK1-NF‑κB Signaling.Journal of inflammation research · 2026Review
- The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases.Progress in neurobiology · 2025Review
- Plasma profiles of neurology-related proteins in at-risk mental state and first-episode psychosis: Associations with psychotic symptoms and cognitive performance.Brain, behavior, & immunity - health · 2025Article
- Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders.bioRxiv : the preprint server for biology · 2025Article
- Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils.Communications biology · 2025Article
- Genome-Wide Association Study of Glucocerebrosidase Activity Modifiers.Molecular neurobiology · 2025Article
- Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.Cells · 2025Review
- Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson's disease risk.Nature aging · 2025Article
- Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.Science advances · 2025Article
- Understanding Parkinson disease in Spain: Genetic and clinical insights.European journal of neurology · 2025Article
- Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.bioRxiv : the preprint server for biology · 2024Article
- Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.Cellular and molecular life sciences : CMLS · 2024Review
- Brain Region-Specific Expression Levels of Synuclein Genes in an Acid Sphingomyelinase Knockout Mouse Model: Correlation with Depression-/Anxiety-Like Behavior and Locomotor Activity in the Absence of Genotypic Variation.International journal of molecular sciences · 2024Article
- Late-onset Krabbe disease presenting as spastic paraplegia - implications of GCase and CTSB/D.Annals of clinical and translational neurology · 2024Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
34 authors at 8 institutions in 5 countries.
Funding
Abstract
backgroundSMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD.
methodsSMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed.
resultsSMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome.
conclusionsOur results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.
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