Lysosomal channel TMEM175 and Parkinson’s disease

Today is World Parkinson’s Day.

Parkinson’s disease, which is commonly recognized by its most well-known symptom, the tremor, now affects over 10 million people worldwide. Some notable individuals, such as actor Michael J. Fox and boxer Muhammad Ali, have been diagnosed with Parkinson’s disease and have significantly contributed to raising awareness of this condition.

Although ion channels might not be the first thing that comes to mind when thinking about genes implicated in Parkinson’s development and progression, several recent studies have identified one particularly interesting ion channel as a genetic risk factor in about 20% of cases of Parkinson’s disease. That ion channel is TMEM175.

A recent study from the Haoxing Xu lab showed that TMEM175 is a proton-activated, proton-selective channel on the lysosomal membrane.

Why is that important and how does this relate to Parkinson’s disease?

In fact, multiple types of evidence support the key role of lysosomal dysfunction in Parkinson’s disease. Many of the Parkinson’s-related genes are involved in the function of lysosomes. Dysfunctional lysosomes have been shown to reduce the ability of cells to degrade proteins, leading to the accumulation of abnormal protein aggregates, which in turn can favor cell death. Therefore, keeping lysosomes in good shape is essential to prevent or retard neuronal degeneration.

You know that lysosomes contain enzymes that break down various cellular components, and in order for these enzymes to be most effective, the pH within the lysosome must be kept somewhere between 4.5 and 5. Anything outside this range may affect the efficiency of lysosomal enzymes. Given the importance of luminal pH for their function, lysosomes have a specific membrane transporter, called the V-ATPase, that pumps protons from the cytosol to the lysosomal lumen to keep their interior acidic.

TMEM175 balances the activity of V-ATPase by mediating the lysosomal proton leak and maintaining lysosome pH homeostasis. It has been shown that TMEM175 deficiency causes lysosomal over-acidification, impairs proteolytic activity, and facilitates α-synuclein aggregation in vivo. Therefore, TMEM175 has emerged as a promising therapeutic target for the treatment of Parkinson’s disease.

As of today, I am aware of three companies developing TMEM175 modulators to increase its activity in patients with Parkinson’s disease: Caraway Therapeutics, which is partnering with AbbVie to develop and market small molecule activators of TMEM175, and Lysoway Therapeutics, which is developing potent modulators of lysosomal ion channels, including TMEM175. It is exciting to see several companies investing in this area of research, and we can only wish them the best of luck.