Dysfunction Of Lysosome Protein TMEM175 Could Be Risk Factor

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by Lindsey Shapiro, PhD |

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A protein called TMEM175 is critically important for maintaining the proper acidity of lysosomes — cellular compartments that clear waste — and its deficiency led to the buildup of the toxic protein alpha-synuclein in the brains of mice.

That finding from a recent study may underlie the previously identified link between mutations in the gene providing instructions for making TMEM175 and the risk of Parkinson’s disease, researchers say.

The study, “Parkinson’s disease-risk protein TMEM175 is a proton-activated proton channel in lysosomes,” was published in Cell

Lysosomes normally work in an acidic environment — one with a low pH — that is carefully coordinated by various molecules. When pH is off-balance, these cellular compartments no longer can perform their functions effectively, leading to the buildup of cellular waste. In Parkinson’s, lysosome dysfunction is thought to contribute to the accumulation of the toxic alpha-synuclein protein, causing cellular stress and brain cell death.

“The lysosome actually needs an optimal pH. Here is an analogy: body temperature has to be 37 degrees Celsius. Thirty-eight is too high and 36 is too low,”  Haoxing Xu, PhD, a professor at the University of Michigan and the study’s lead author, said in a press release.

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“The enzymes in lysosomes require a pH optimum of roughly 4.6. Anything outside of 4.6 pH may cause metabolic dysfunction, and therefore accumulation of cellular garbage, which will eventually cause neurodegeneration and metabolic diseases,” Xu added.

Mutations in the gene encoding TMEM175 have been identified as risk factors for Parkinson’s development, but the protein was previously thought to predominately play a role in transporting potassium.

The research team now identified that TMEM175 was critically involved in maintaining this pH equilibrium in lysosomes.

Protons — positively charged particles — inside the cell make it more acidic, whereas their exit makes it less so. While it was already known that a protein called V-ATPase works to bring protons inside the cell, it was not known which mechanisms were in place to counterbalance V-ATPase and prevent over-acidification.

“We were interested that if there was the V-ATPase to pump a proton in, lysosomes must have an ion channel protein to release the proton when the proton level was too high inside the lysosome,” Xu said.

In a cell culture screening assay of proteins known to be present on the surface of lysosomes, the researchers found that TMEM175, which was highly permeable to protons, was necessary for their ability to flow out of the cell.

“As soon as one realized that TMEM175 was probably a proton channel, then the rationale for how a mutation of that protein could cause Parkinson’s seemed pretty obvious,” said Richard Hume, PhD, a University of Michigan professor and an author of the study.

To validate their findings, the researchers measured the acidity of lysosomes when TMEM175 was removed from cells in culture. When the protein was lacking, the lysosomes could not maintain their steady-state pH, and enzymes needed to break down cellular waste were dysfunctional.

In mice lacking TMEM175, the researchers saw similar effects. Notably, mice without TMEM175 also showed marked accumulations of alpha-synuclein in their brain cells, providing a potential link between TMEM175 dysfunction and Parkinson’s development.

“In the end, we are very confident that this is the protein that’s controlling the proton leak in the lysosome,” Xu said. “This paper is exciting because mutations in this protein happen to be high risk for Parkinson’s disease.”

Overall, the findings provide “proof of concept that modulation of TMEM175 activity in the lysosome could help develop therapies for neurodegenerative diseases,” the researchers wrote.

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