June 26, Science and Technology Daily reporter learned from Zhejiang University of Technology, the university’s Yangtze River Delta Green Pharmaceutical Collaborative Innovation Center lysosomal new drug development team and the University of Michigan Professor Hao-Xin Xu’s team to find the lysosomal maintenance of acidic environment of hydrogen ion channel TMEM175, and reveal its potential association with Parkinson’s disease, so as to discover the key pathogenic mechanism of Parkinson’s disease. The related paper was recently published in the journal Cell.
Lysosomes are the “waste disposal centers” of cells, and their special acidic environment and various acidic hydrolases can degrade and reuse “waste” such as damaged organelles. Previously, genome-wide association studies revealed that mutations in certain genes closely related to lysosomal function are highly associated with the risk of Parkinson’s disease, with about 20% of Parkinson’s patients having mutations in the TMEM175 gene.
”It is useful to understand the lysosome as the stomach, where an imbalance in its acidic environment, which interferes with normal function, can trigger indigestion or even cause disease. Cell biologists have found that in order to maintain an acidic environment at pH 4.6, the hydrogen ion pump V-ATPase on the lysosomal membrane can consume energy at the expense of continuously pumping hydrogen ions from the cytoplasm to the lysosome.” Dr. Meiqin Hu, the first author of the paper, explained that it is like a reservoir maintaining water level, with an inlet pump and a floodgate. The lysosomal membrane should also have corresponding ion channels to mediate hydrogen ion efflux, which is used to maintain a stable acidic environment.
The joint team collaborated intensively and used lysosomal membrane clamp technology to find out that TMEM175 is the lysosomal floodgate and will only be activated in the acidic environment of the lysosome lumen through expression screening. When TMEM175 is mutated, lysosomal acidity and lysosomal function will be too high, resulting in excessive accumulation of cellular metabolites in the lysosome, causing cellular damage and triggering neurodegenerative diseases such as Parkinson’s disease. This conclusion was also verified in the neural cell model of Parkinson’s disease and mouse model built by the team.
The joint team introduced that the development of targeted drugs based on the regulation of TMEM175 is expected to be used in the prevention and treatment of Parkinson’s disease, a neurodegenerative disease closely related to lysosomal metabolism and degradation, and lysosomal storage diseases.
