TMEM175, a transmembrane protein, is an ion channel in the lysosomal membrane [1]. It is crucial for maintaining lysosomal acidity, coordinating with V-ATPase to modulate the luminal pH of lysosomes, which is essential for the digestion of abnormal proteins and organelles [1]. Lysosomal function is closely related to multiple biological processes, and TMEM175 is associated with neurological disorders [1]. Genetic models are valuable for studying its function.

TMEM175 deficiency in a neuronal model system led to unstable lysosomal pH, decreased lysosomal catalytic and glucocerebrosidase activities, impaired autophagosome clearance, and decreased mitochondrial respiration [2]. In rat primary neurons, it increased susceptibility to exogenous α -synuclein fibrils, with more phosphorylated and detergent -insoluble α -synuclein deposits [2]. In a 1 -methyl -4 -phenyl -1,2,3,6 -tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout of TMEM175 mitigated motor impairment and dopaminergic neuron loss [4]. Also, in neonatal rats with hypoxic -ischemic brain injury, downregulation of TMEM175 impaired the autophagy -lysosome pathway, while overexpression mitigated neuronal injury and improved cognitive function [3].

In conclusion, TMEM175 is essential for maintaining lysosomal and mitochondrial function. Its knockout or down -regulation in relevant animal models reveals its significant role in neurological diseases, especially Parkinson's disease and neonatal hypoxic -ischemic brain injury. These findings suggest TMEM175 could be a potential therapeutic target for treating such diseases.

References:

1. Wu, Luojia, Lin, Yue, Song, Jiali, Hua, Fuzhou, Ying, Jun. 2023. TMEM175: A lysosomal ion channel associated with neurological diseases. In Neurobiology of disease, 185, 106244. doi:10.1016/j.nbd.2023.106244. https://pubmed.ncbi.nlm.nih.gov/37524211/

2. Jinn, Sarah, Drolet, Robert E, Cramer, Paige E, Tadin-Strapps, Marija, Stone, David J. 2017. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation. In Proceedings of the National Academy of Sciences of the United States of America, 114, 2389-2394. doi:10.1073/pnas.1616332114. https://pubmed.ncbi.nlm.nih.gov/28193887/

3. Zhang, Huiyi, Tian, Ye, Yu, Weiwei, Li, Xinsheng, Xu, Ying. 2023. TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic-ischemic brain injury. In Journal of cellular physiology, 238, 2512-2527. doi:10.1002/jcp.31096. https://pubmed.ncbi.nlm.nih.gov/37566721/

4. Qu, Lili, Lin, Bingqian, Zeng, Wenping, Liu, Dan, Cang, Chunlei. 2022. Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease. In EMBO reports, 23, e53234. doi:10.15252/embr.202153234. https://pubmed.ncbi.nlm.nih.gov/35913019/