A rare TMEM175 mutation drives Parkinson's disease pathology by disrupting proton gating and lysosomal acidification.
7 affiliations
- 1New Cornerstone Science Laboratory & Liangzhu Laboratory, the Second Affiliated Hospital & School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.
- 2Department of Neurology, the Second Affiliated Hospital and
- 3Departments of Pharmacology and Pathology, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 4Department of Biophysics, the School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.
- 5Zhejiang Key Laboratory of Pain Perception and Neuromodulation, Hangzhou, China.
- 6Institute of Fundamental and Transdisciplinary Research & The State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China.
- 7Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
Abstract
Transmembrane protein 175 (TMEM175), implicated in Parkinson's disease (PD) risk, has been variably proposed to function as a background K+ "leak" channel or a proton-activated proton channel in lysosomes. Here, we identified the rare TMEM175 variant p.L275R in a patient with early onset PD. Electrophysiological analyses revealed that TMEM175-L275R mutant proteins retain normal lysosomal expression and K+ "leak" activity, but specifically lose proton- and agonist-dependent activation gating. In skin fibroblasts isolated from the patient with PD harboring the monoallelic p.L275R mutation (TMEM175+/L275R), and in derived induced pluripotent stem cells and induced dopaminergic neurons, lysosomal H+ flux, acidification, and degradation were impaired. These lysosomal defects were corrected upon genome editing to produce the isogenic WT allele (+/+Cor), but appeared when the mutant allele was introduced onto a WT background (+/L275RMut). Pathological α-synuclein aggregation was facilitated in patient-derived (+/L275R) and mutation-introduced (+/L275RMut) neurons. Consistent with these genetic findings, pharmacological activation of TMEM175 with small-molecule agonists restored lysosomal functions and reduced α-synuclein aggregation in TMEM175+/L275R neurons. In in-vivo studies, equivalent-site-mutation knock-in mice demonstrated synucleinopathy and PD-like motor phenotypes. Collectively, our work provides genetic and pharmacological evidence that severe loss-of-function mutations may contribute causally to the onset age and pathogenesis of PD and identifies lysosomal proton channels and transporters as potential therapeutic targets for PD intervention.
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BibTeX
@article{yang2026rare,
title = {{A rare TMEM175 mutation drives Parkinson's disease pathology by disrupting proton gating and lysosomal acidification.}},
author = {Xiaotong Yang and Ping Li and Man Lv and Lingyong Wang and Ruyi Shan and Zikai Jiang and Danzhen Chen and Fangqian Huang and Weijie Cai and Liding Zhao and Zuoyou Guo and Xinhui Chen and Zhidong Cen and Yichang Wang and Wei Yang and Xinran Li and Wei Luo and Lin Yang and Meiqin Hu and Haoxing Xu},
journal = {The Journal of clinical investigation},
year = {2026},
month = nov,
doi = {10.1172/jci206733},
url = {https://europepmc.org/article/MED/42969231},
note = {CC BY},
}
RIS
TY - JOUR
TI - A rare TMEM175 mutation drives Parkinson's disease pathology by disrupting proton gating and lysosomal acidification.
AU - Xiaotong Yang
AU - Ping Li
AU - Man Lv
AU - Lingyong Wang
AU - Ruyi Shan
AU - Zikai Jiang
AU - Danzhen Chen
AU - Fangqian Huang
AU - Weijie Cai
AU - Liding Zhao
AU - Zuoyou Guo
AU - Xinhui Chen
AU - Zhidong Cen
AU - Yichang Wang
AU - Wei Yang
AU - Xinran Li
AU - Wei Luo
AU - Lin Yang
AU - Meiqin Hu
AU - Haoxing Xu
PY - 2026
DA - 2026/11/02
JO - The Journal of clinical investigation
DO - 10.1172/jci206733
UR - https://europepmc.org/article/MED/42969231
AB - Transmembrane protein 175 (TMEM175), implicated in Parkinson's disease (PD) risk, has been variably proposed to function as a background K+ "leak" channel or a proton-activated proton channel in lysosomes. Here, we identified the rare TMEM175 variant p.L275R in a patient with early onset PD. Electrophysiological analyses revealed that TMEM175-L275R mutant proteins retain normal lysosomal expression and K+ "leak" activity, but specifically lose proton- and agonist-dependent activation gating. In skin fibroblasts isolated from the patient with PD harboring the monoallelic p.L275R mutation (TMEM175+/L275R), and in derived induced pluripotent stem cells and induced dopaminergic neurons, lysosomal H+ flux, acidification, and degradation were impaired. These lysosomal defects were corrected upon genome editing to produce the isogenic WT allele (+/+Cor), but appeared when the mutant allele was introduced onto a WT background (+/L275RMut). Pathological α-synuclein aggregation was facilitated in patient-derived (+/L275R) and mutation-introduced (+/L275RMut) neurons. Consistent with these genetic findings, pharmacological activation of TMEM175 with small-molecule agonists restored lysosomal functions and reduced α-synuclein aggregation in TMEM175+/L275R neurons. In in-vivo studies, equivalent-site-mutation knock-in mice demonstrated synucleinopathy and PD-like motor phenotypes. Collectively, our work provides genetic and pharmacological evidence that severe loss-of-function mutations may contribute causally to the onset age and pathogenesis of PD and identifies lysosomal proton channels and transporters as potential therapeutic targets for PD intervention.
SN - 0021-9738
SN - 1558-8238
ER -