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

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 TMEM1 75, 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 alpha-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.

Automated summary

A genetic risk factor for Parkinson's disease, TMEM175, acts as a proton-activated, proton-selective channel on the lysosomal membrane to regulate lysosomal H+ leak. Activation of TMEM175 stops further acidification of lysosomes beyond the normal range. Deficiency of TMEM175 causes lysosomal over-acidification, impaired proteolytic activity, and facilitates alpha-synuclein aggregation.