TMEM175

Transmembrane Protein 175 (TMEM175) is a conserved lysosomal and late endosomal potassium channel, alternatively named KCNN4L. Characterized by a six-transmembrane domain architecture, it displays pH-dependent and weakly voltage-gated activity, mediating K+ efflux to balance lysosomal membrane potential and maintain acidic pH—critical for optimal lysosomal hydrolase activity and fusion with autophagosomes. TMEM175 intersects with autophagic signaling and mTORC1 nutrient-sensing pathways; its loss-of-function impairs autophagic flux and lysosomal biogenesis.
Pathogenic mutations in TMEM175 (e.g., the missense variant p.M393T) are linked to familial Parkinson’s disease (PD), as they disrupt lysosomal K+ homeostasis, leading to impaired α-synuclein clearance and accumulation of toxic aggregates—core pathological features of PD. Preclinical investigations validate TMEM175 as a therapeutic target: small-molecule activators restore lysosomal function in PD patient-derived cells and animal models, reducing α-synuclein pathology. While no clinical-stage drugs targeting TMEM175 exist yet, ongoing structure-based drug design efforts aim to develop selective modulators for neurodegenerative disorders.