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Cited by 254Calcium signaling and nucleotide metabolismCellular transport and secretionParkinson's Disease Mechanisms and Treatments

Parkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes

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Hu, Meiqin, Li, Ping, Wang, Ce, Feng, Xinghua, Geng, Qi, Chen, Wei, Marthi, Matangi, Zhang, Wenlong +6 more·2022·Cell
DOI 10.1016/j.cell.2022.05.021PMC PMC9236176
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Abstract

Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules. This pH optimum is maintained by proton influx produced by the V-ATPase and efflux through an unidentified "H+ leak" pathway. Here we show that TMEM175, a genetic risk factor for Parkinson's disease (PD), mediates the lysosomal H+ leak by acting as a proton-activated, proton-selective channel on the lysosomal membrane (LyPAP). Acidification beyond the normal range potently activated LyPAP to terminate further acidification of lysosomes. An endogenous polyunsaturated fatty acid and synthetic agonists also activated TMEM175 to trigger lysosomal proton release. TMEM175 deficiency caused lysosomal over-acidification, impaired proteolytic activity, and facilitated α-synuclein aggregation in vivo. Mutational and pH normalization analyses indicated that the channel's H+ conductance is essential for normal lysosome function. Thus, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology.

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  • In Parkinson's disease, tremor, bradykinesia and other motor symptoms correlate with alpha-synuclein-containing Lewy body inclusions in the substantia nigra.

    “In Parkinson’s disease (PD), tremor, bradykinesia and other motor symptoms correlate with alpha-synuclein-containing Lewy body inclusions in the substantia nigra.75”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [75]

    The Results section on TMEM175 deficiency says that α-synuclein aggregation is a hallmark of Parkinson’s disease and that phosphorylated α-synuclein accumulates in Lewy body inclusions. It does not link those inclusions in the substantia nigra to tremor, bradykinesia, or other motor symptoms; its reported aggregation experiment concerns the striatum of mice. No page number is available in our copy. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Hu, M., Li, P., Wang, C., Feng, X., Geng, Q., Chen, W., Marthi, M., Zhang, W., Gao, C., Reid, W., Swanson, J., Du, W., Hume, R. I., & Xu, H.
Affiliations
  • University of Michigan (US)
  • Second Affiliated Hospital of Zhejiang University (CN)
  • Northeast Agricultural University (CN)
Corresponding author
  • Hu, Meiqin
  • Xu, Haoxing
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2022-06
Volume
185
Issue
13
Pages
2292-2308.e20
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2022.05.021
PMC
PMC9236176
OpenAlex
W4283367225
Cited by
254
References
5
Citations by year
2026: 63 · 2025: 74 · 2024: 60 · 2023: 47 · 2022: 10
FWCI
30.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (R35GM131720)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115474)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
TMEM175, Parkinson's disease, lysosomal acidification, lysosomal membrane, V-ATPase, polyunsaturated fatty acids, alpha-synuclein aggregation, proteolytic activity, endosomal pH
MeSH terms
Humans, Hydrogen-Ion Concentration, Intracellular Membranes, Lysosomes, Parkinson Disease, Protons, Endosomes, Potassium Channels

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