Trafficking Deficiency of TMEM175 Variants in Parkinson's Disease Pathogenesis and the Prospects of Precision Medicine

The transmembrane protein 175 (TMEM175) is a high-risk gene for Parkinson's disease (PD) and encodes an ion channel in lysosomes. Many PD-associated variants in TMEM175 lead to the loss of ion channel function. In this study, we identified the PD-associated TMEM175-L156P variant is a missense mutation with trafficking deficiency. Using imaging, biochemical, and whole-endolysosomal electrophysiological approaches, we identified that L156P abolished the lysosomal expression of TMEM175; instead, it accumulates in the endoplasmic reticulum (ER). The cytosolic segment of the fourth transmembrane helix (TM4-1), where the L156 resides, determined the lysosomal localization of TMEM175. Having understood the structural basis, we evaluated wild-type (WT) TMEM175 and pharmacological chaperones previously used in cystic fibrosis treatment. We elucidated that WT partially rescued the aberrant expression of L156P. Moreover, the chaperones substantially reduced the ER-retained L156P and facilitated its trafficking to lysosomes. We further screened and identified a bifunctional chemical molecule that both corrected the trafficking defects and potentiated the ion channel function of L156P. Notably, the chemical-restored L156P is functional, as it relieves the lysosomal over-acidification. Conclusively, we establish the relationship between aberrant trafficking and pathogenesis in PD, demonstrating the potential of utilizing "chaperone plus agonist" bifunctional chemical molecules as personalized treatment for PD.