ArticleHuman molecular genetics2019
Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 1 of them a synthesis that pooled it.
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Who cites it
60 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
- Multi-ancestry genome-wide association meta-analysis of Parkinson's disease.Nature genetics · 2024Pooled it
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- A nonhydrolyzable candesartan cilexetil analog reveals synergistic activation as a tractable mechanism for TMEM175 modulation.American journal of physiology. Cell physiology · 2026Article
- TMEM175 rescues post-infarct cardiac dysfunction via mTORC1-lysosomal axis modulation.Acta pharmacologica Sinica · 2026Article
- Gaps in the Parkinson's disease therapeutic clinical pipeline: A focus on approaches targeting disease pathobiology.Journal of Parkinson's disease · 2026Review
- Single-cell eQTL mapping reveals convergent glial-neuronal risk architecture in Parkinson's disease.bioRxiv : the preprint server for biology · 2026Article
- Regional gene expression and brain atrophy in dementia with Lewy bodies: an imaging transcriptomics study.NPJ Parkinson's disease · 2026Article
- Clathrin-mediated endocytosis as an axis for the etiopathogenesis of Parkinson's disease.Journal of cell science · 2026Review
- Benchmarking Lysosome Enrichment Methods: A Guide for Research and Clinical Translation.Analytical chemistry · 2026Article
- Macrophage TMEM175-Mediated Transcriptional Regulation of Cathepsins Drives Bacterial Killing in Sepsis.Journal of immunology research · 2026Article
- Lysosomal pH Measurements via Dual-Imaging Microscopy.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- TMEM175, SCARB2 and CTSB associations with Parkinson's disease risk across populations.NPJ Parkinson's disease · 2025Article
- Tackling a disease on a global scale, the Global Parkinson's Genetics Program, GP2: A new generation of opportunities.American journal of human genetics · 2025Review
- Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.Aging and disease · 2025Review
- Prioritizing Parkinson's disease risk genes in genome-wide association loci.NPJ Parkinson's disease · 2025Article
- Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches.Bioelectricity · 2025Review
- Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson's disease patients mutated in TMEM175.NPJ Parkinson's disease · 2025Article
- What We Know About TMEM175 in Parkinson's Disease.CNS neuroscience & therapeutics · 2025Review
- Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases.Nature reviews. Molecular cell biology · 2024Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.M393T) in TMEM175, which is 20 orders of magnitude more significant than any other SNP in the region. Because TMEM175 is a lysosomal gene that has been shown to influence α-synuclein phosphorylation and autophagy, the p.M393T variant is an attractive candidate, and we have examined its effect on TMEM175 protein and PD-related biology. After knocking down each of the genes located under the GWAS peak via multiple shRNAs, only TMEM175 was found to consistently influence accumulation of phosphorylated α-synuclein (p-α-syn). Examination of the p.M393T variant showed effects on TMEM175 function that were intermediate between the wild-type (WT) and knockout phenotypes, with reduced regulation of lysosomal pH in response to starvation and minor changes in clearance of autophagy substrates, reduced lysosomal localization, and increased accumulation of p-α-syn. Finally, overexpression of WT TMEM175 protein reduced p-α-syn, while overexpression of the p.M393T variant resulted in no change in α-synuclein phosphorylation. These results suggest that the main signal in the chromosome 4p16.3 PD risk locus is driven by the TMEM175 p.M393T variant. Modulation of TMEM175 may impact α-synuclein biology and therefore may be a rational therapeutic strategy for PD.
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