ArticleJournal of the American Chemical Society2024
Discovery of Selective Inhibitors for the Lysosomal Parkinson's Disease Channel TMEM175.
Article in Journal of the American Chemical Society, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Deficiency of lysosomal TMEM175 in myeloid macrophages exerts anti-tumor immunity via inflammasome and cross-presentation pathway.Nature communications · 2026Article
- Targeting TMEM175 in Lysosomal Physiology and Human Diseases.Current stem cell research & therapy · 2026Review
- Macrophage TMEM175-Mediated Transcriptional Regulation of Cathepsins Drives Bacterial Killing in Sepsis.Journal of immunology research · 2026Article
- Transmembrane protein TMEM98 as a multifunctional regulator in cancer: from signaling pathways to translational implications.Journal of translational medicine · 2025Review
- Progress in Disease-Modifying Therapies for Parkinson's Disease.Aging and disease · 2025Review
- TMEM175 activity in BK-deficient macrophages maintains lysosomal function and mediates silica-induced inflammatory response in macrophages.Inhalation toxicology · 2025Article
- Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches.Bioelectricity · 2025Review
- Unraveling pH Regulation of TMEM175, an Endolysosomal Cation Channel With a Role in Parkinson's Disease.Journal of cellular physiology · 2025Review
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
TMEM175 is a lysosomal potassium and proton channel that is associated with the development of Parkinson's disease. Advances in understanding the physiological roles of TMEM175 have been hampered by the absence of selective inhibitors, and studies involving genetic perturbations have yielded conflicting results. Here, we report the discovery and characterization of the first reported TMEM175-selective inhibitors, 2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of human TMEM175 bound by 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6 increases the level of lysosomal macromolecule catabolism, thereby accelerating macropinocytosis and other digestive processes. These inhibitors may serve as valuable tools to study the roles of TMEM175 in regulating lysosomal function and provide useful templates for future therapeutic development in Parkinson's disease.
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Registered trials
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