TMEM175: a lysosome channel

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

The International Parkinson's Disease Genomics Consortium (Mike Nalls, Andrew Singleton and many others, 2014); Cang, Ren and colleagues (2015) and Riederer, Ren and colleagues (2026); Jinn, Stone and colleagues (2017, 2019, the latter with Blauwendraat, Nalls and Singleton); Krohn, Gan-Or and colleagues (2020); Hu, Xu and colleagues (2022); Zheng, Fu and colleagues (2022); and Spencer Freeman, Sergio Grinstein and colleagues for the 2026 commentary.

What happened

• 2014: A genome-wide study of 13,708 cases and 95,282 controls found 26 genome-wide significant loci; 24 replicated in a further 5,353 cases and 5,551 controls, 6 of them new, for 28 independent risk variants across 24 loci. A chromosome 4 locus (GAK-DGKQ) that covers several genes, TMEM175 among them, carries a second independent variant. Nat Genet 46:989–993.
• 2015: Cang et al. identified TMEM175 as a major potassium channel in endosome and lysosome membranes (Cell 162:1101–1112).
• 2017: Lowering TMEM175 in rat neurons destabilised lysosomal pH, lowered glucocerebrosidase activity and mitochondrial respiration, and increased phosphorylated, insoluble synuclein after fibril exposure (Jinn et al., PNAS 114:2389–2394).
• 2019–20: Two groups pointed to coding variants as the cause of the locus signal. Jinn et al. (Hum Mol Genet 28:3244–3254) found p.M393T (rs34311866) the most significant SNP in the region and, in cells, partly impaired lysosomal pH control and increased phosphorylated synuclein. Krohn et al. (Ann Neurol 87:139–153) sequenced 1,575 cases, 533 REM sleep behaviour disorder patients and 1,583 controls: p.M393T raised risk (odds ratio 1.37) and was linked to lower GCase activity; p.Q65P lowered it (odds ratio 0.72).
• 2022: Hu et al. (Cell 185:2292) argued TMEM175 is mainly a proton-selective channel, and that its loss over-acidified lysosomes and promoted synuclein aggregation in vivo. Zheng et al. (Sci Adv 8:eabm1568) found it passes both potassium and protons.
• 2026: Riederer et al. (J Cell Biol 225:e202501145) reported that in lysosomes it mainly conducts potassium and is not a proton-selective channel. Freeman and Grinstein's commentary called its role in Parkinson's "unquestionable" but its mechanism unresolved.

Why it moved us toward a cure

It is one of the clearest genetic links from a risk signal to a druggable-looking lysosome component, joining GBA, ATP13A2 and others (landmark 16, landmark 45, landmark 19).

Outcome

Open. Whether TMEM175 should be switched on or off, and by what drug, is unknown; the 2026 commentary even cautions against proton-leak drugs. No clinical trial was found.

Sources

• Nalls et al., Nat Genet 2014;46:989–993, DOI 10.1038/ng.3043
• Science of Parkinson's, "The modification of acidification" (review of 2014–2022 papers)
• Alzforum comments on Zheng et al., Sci Adv 2022
• Freeman and Grinstein commentary, J Cell Biol 2026;225(1):e202511084
• Cang et al., Cell 2015, DOI 10.1016/j.cell.2015.08.002 · Jinn et al., PNAS 2017, DOI 10.1073/pnas.1616332114 · Jinn et al., Hum Mol Genet 2019, DOI 10.1093/hmg/ddz136 · Krohn et al., Ann Neurol 2020, DOI 10.1002/ana.25629
• Hu et al., Cell 2022, DOI 10.1016/j.cell.2022.05.021 · Zheng et al., Sci Adv 2022, DOI 10.1126/sciadv.abm1568 · Riederer et al., J Cell Biol 2026, DOI 10.1083/jcb.202501145
• No correction or retraction was found for these papers in Crossref or Europe PMC (the Crossref check for the 2026 paper failed); PubPeer could not be reached.
• Not yet verified: the Freeman and Grinstein wording (page returned 403 this time; taken from the earlier check); whether the variants act through lysosomal pH or GCase activity; any drug programme.