As the overall life span of humans increases, neurodegenerative diseases pose an increasing threat to human health. Parkinson's disease (Parkinson's Disease, PD) is the most common neurodegenerative disease. Its pathogenesis has not been clear. How related risk genes induce Parkinson's disease has become a current research topic in the scientific and medical circles. Hotspot.
Recently, in a new study published on "Cell" , the lysosome new drug research and development team from the Yangtze River Delta Green Pharmaceutical Collaborative Innovation Center of Zhejiang University of Technology collaborated with the team of Professor Xu Haoxin of the University of Michigan to find a solution for The HT2 channel protein , key for the enzymatic maintenance of its acidic environment, reveals its potential link to Parkinson's disease. The study found that TMEM175, a risk gene for Parkinson's disease, is a hydrogen ion channel activated by hydrogen ions and located in lysosomes, and its mutation is one of the key factors that may induce Parkinson's disease.
As an important acidic organelle in cells, lysosomes are the "garbage disposal stations" within cells. Its special acidic environment (pH 4.6) and the various acidic hydrolases it contains can degrade and reuse "junk" such as intracellular macromolecules, damaged organelles , etc., and the degradation and reuse function of lysosomes Essential for normal cell growth and function. In order to study how the acidic environment within lysosomes is maintained, cell biologists have previously discovered a channel that transports hydrogen ions inward - the hydrogen ion pump V-ATPase on the lysosomal membrane of .
If V-ATPase keeps working and the pH value in the lysosome is too low (4.6), is there a corresponding ion channel on the lysosomal membrane to mediate the flow of hydrogen ions out of the lysosome? Is it to help 'discharge' excess hydrogen ions in lysosomes?
Professor Xu Haoxin, who has been engaged in research on lysosomal ion channels for many years, began to think about this issue. Professor Xu boldly innovated on the basis of traditional patch clamp technology and invented lysosomal patch clamp technology. This technology has successfully achieved direct recording of ion channel currents on lysosomal membranes, greatly advancing the study of ion channels on lysosomes, so it has also become possible to directly record hydrogen ion channel currents.
In this new study, the researchers used lysosomal patch clamp technology and expression screening methods to discover the hydrogen ion "floodgate"-TMEM175, which is the lysozyme that scientists have been searching for for decades. Body hydrogen ion channel .
In previous studies, TMEM175 was thought to be just a potassium ion channel on the lysosomal membrane. This study shows that in the acidic environment (pH 4.6) of lysosomal physiological conditions, the permeability of TMEM175 to hydrogen ions and potassium ions is 50,000 to one. In layman's terms, the ions flowing through the TMEM175 channel are about There is only one potassium ion in 50,000, and the rest are all hydrogen ions. More importantly, this "floodgate" is very "intelligent". It will only be opened when the acidity in the lysosome cavity is too high (pH4.6), which allows the pH value of in the lysosome to reach a dynamic equilibrium.
After a series of further verifications, the research team finally confirmed that TMEM175 is a hydrogen ion channel (lysosomal, proton-activated, proton-permeant channel, LyPAP) on the lysosome that is activated by hydrogen ions.
Based on the above-mentioned major findings, the research team further searched for the potential relationship between TMEM175 and Parkinson's disease. Previously, the genome-wide association study (GWAS) revealed that mutations in certain genes closely related to lysosomal function are highly associated with the risk of Parkinson's disease. About 20% of Parkinson's disease patients have mutations in TMEM175. This early discovery is The team’s follow-up research provided direction and ideas.
To this end, the research team began to explore the potential mechanism by which impaired function of the "flood gate" TMEM175 induces Parkinson's disease. Research has found that V-ATPase on the lysosomal membrane works synergistically with TMEM175 to achieve a dynamic balance of hydrogen ion concentration in the lysosome, that is, a stable pH, by regulating the pumping in and outflow of hydrogen ions, thus ensuring its normal physiology. Function.
When TMEM175 mutates and its function decreases, it will cause the lysosomal acidity to be too high and the lysosomal degradation function to weaken, etc., which will lead to the accumulation of cell metabolites in the lysosome, causing cell damage, and then inducing Parkinson's disease. neurodegenerative diseases. This conclusion has also been verified in neuronal cell models and mouse models of Parkinson's disease.
V-ATPase and TMEM175 cooperate to maintain the normal pH value of lysosomes
TMEM175-deficient mice are more susceptible to being induced by fiber-like α-synuclein to produce Lewy bodies, a marker of PD.
The team stated that many The team is developing targeted drugs for regulating lysosomal ion channels, including TRPML1 and TMEM175, which may be used in the future to prevent and treat neurodegenerative diseases related to lysosomal metabolic degradation, such as Parkinson's disease and Alzheimer's disease. Heimer's disease , etc.
paper link:
https://doi.org/10.1016/j.cell.2022.05.021
