Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson’s Disease

Abstract

Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 (TMEM175) is a unique lysosomal potassium channel that shares little sequence similarity with other potassium channels. It is found in bacteria, archaea, and animals. The prokaryotic TMEM175 consists of one six-transmembrane domain that adopts a tetrameric architecture, while the mammalian TMEM175 is comprised of two six-transmembrane domains that function as a dimer in lysosomal membranes. Previous studies have demonstrated that the lysosomal K+ conductance mediated by TMEM175 is critical for setting membrane potential, maintaining pH stability, and regulating lysosome–autophagosome fusion. AKT and B-cell lymphoma 2 regulate TMEM175’s channel activity through direct binding. Two recent studies reported that the human TMEM175 is also a proton-selective channel under normal lysosomal pH (4.5–5.5) as the K+ permeation dramatically decreased at low pH while the H+ current through TMEM175 greatly increased. Genome-wide association studies and functional studies in mouse models have established that TMEM175 is implicated in the pathogenesis of Parkinson’s disease, which sparks more research interests in this lysosomal channel.

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson’s disease risk genes

“…TMEM175 is a widely expressed lysosomal membrane protein that serves as a proton-activated, proton-selective channel, mediating lysosomal H+ efflux. TMEM175 deficiency is associated with impaired intracellular protein hydrolysis activity and the aggregation of α-synuclein [ 38 , 39 ]. We also noticed enrichment of specific lysosome related pathways in the TWAS analysis in 79 identified genes based on CNS prediction models and 95 identified genes based on all tissues ( Supplementary Figures 5 , 6 ), supported the hypothesis that the genes associated with PD identified in this study are a subset of genes with similar biological functions and interactions, of which the lysosomal pathway play a crucial role in the pathogenesis of PD [ 40 , 41 ].…”

The Impact of 90 Parkinson’s Disease-Risk Single Nucleotide Polymorphisms on Urinary Bis(monoacylglycerol)phosphate Levels in the Prodromal and PD Cohorts

“…Rs34311866 is a missense SNP in transmembrane protein 175 (TMEM175). TMEM175 is a lysosomal ion channel protein, and the missense variants of its two SNPs, rs34311866 (M393T) and rs34884217 (Q65P), are highly related to PD [58]. The former was identified to increase the risk of PD, while the latter was just the opposite [59].…”

Research Progress on the Pathogenesis, Diagnosis, and Drug Therapy of Alzheimer’s Disease

“…Its main symptoms are motor dysfunctions, but PD patients also suffer from comorbid non-motor symptoms, including cognitive decline, sleep disorder, and depression. Furthermore, its patterns of progression vary considerably across individuals [ 4 , 5 , 6 ]. ALS is a fatal neurodegenerative disease.…”