U-M研究者がパーキンソン病のリスクに関する新たな分子メカニズムを解明(U-M researchers reveal new molecular mechanism for Parkinson’s disease risk)


2022-06-23 ミシガン大学



パーキンソン病リスクタンパク質TMEM175はリソソームでプロトン活性化されるプロトンチャネルである Parkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes

Meiqin Hu ,Ping Li ,Ce Wang ,Xinghua Feng,Qi Geng,Wei Chen,Matangi Marthi,Wenlong Zhang,Chenlang Gao,Whitney Reid,Joel Swanson,Wanlu Du,Richard I. Hume,Haoxing Xu
Cell  Published:JUNE 23, 2022


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.