TMEM175 Gene: Function, Mutations, and Parkinson's Disease Risk

The TMEM175 gene encodes a transmembrane protein that functions as a potassium (K+) channel on the lysosomal membrane. It is a critical component for maintaining lysosomal pH stability and membrane potential, which are essential for proper cellular waste degradation and autophagy. TMEM175 is highly expressed in the brain and has emerged as a significant genetic risk factor for Parkinson's disease (PD). Genome-wide association studies (GWAS) have identified common variants in TMEM175 that increase the risk of developing PD, while rare coding mutations have been linked to early-onset forms of the disease. The protein forms a unique potassium channel with a novel structure, distinct from other known potassium channels, making it a promising therapeutic target for neurodegenerative diseases.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Lysosomal acidification and ion homeostasis

• Autophagy (macroautophagy)

• Parkinson's disease pathway

• Endocytosis

The TMEM175 protein is a 477-amino acid lysosomal potassium channel with a unique architecture, consisting of two tandem 6-transmembrane (TM) domains that form a single functional channel. It is a homodimer, and each subunit contributes to the pore. Unlike classical potassium channels, TMEM175 lacks a typical selectivity filter signature sequence, yet it is highly selective for K+ over Na+. The channel is constitutively active and is crucial for setting the lysosomal membrane potential and providing the electrical driving force for proton (H+) entry via the V-ATPase, thereby maintaining the acidic luminal pH required for lysosomal enzyme activity. TMEM175 also interacts with other lysosomal proteins and is involved in the fusion of autophagosomes with lysosomes. Its dysfunction leads to impaired clearance of cellular debris, particularly in neurons, contributing to neurodegeneration.