A rare TMEM175 mutation drives Parkinson's disease pathology by disrupting proton gating and lysosomal acidification.

The rare TMEM175 p.L275R mutation in an early-onset Parkinson’s disease patient disrupts proton- and agonist-dependent activation gating while preserving lysosomal expression and K+ leak activity.

• Why it matters: TMEM175 has been proposed to regulate lysosomal ion homeostasis, but the specific functional defect linking a rare variant to Parkinson’s pathology was unclear.
• What they did: The study combined electrophysiology with patient skin fibroblasts, iPSCs, induced dopaminergic neurons, genome editing to isogenic WT, and small-molecule TMEM175 agonists; it also used equivalent-site-mutation knock-in mice.
• The result: In TMEM175+/L275R cells and neurons, lysosomal H+ flux, acidification, degradation, and α-synuclein aggregation were impaired or increased, and these defects were rescued by genome editing or agonists, with knock-in mice showing synucleinopathy and PD-like motor phenotypes.

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