TMEM175 is a transmembrane protein that regulates the internal environment of cellular compartments. It has garnered scientific attention due to its role in maintaining cellular health.
Cellular Function of TMEM175
TMEM175 is primarily located in the membranes of lysosomes, which are small, membrane-bound sacs within cells often referred to as the cell’s recycling and waste disposal centers. Lysosomes contain various enzymes that break down cellular waste products, old organelles, and foreign materials. For these enzymes to function properly, the lysosomal interior must maintain an acidic pH, typically ranging between 4.5 and 5.0.
TMEM175 functions as an ion channel, facilitating ion movement across the lysosomal membrane. It acts as both a potassium (K+) channel and a proton (H+) channel, depending on the pH. At higher pH levels, it regulates potassium ion flow, which helps maintain the lysosomal membrane potential.
At lower, more acidic pH levels (below pH 4.6), TMEM175 transitions to function as a proton-activated proton channel, mediating the outflow of protons from the lysosome. This proton leak mechanism balances the activity of the V-ATPase, a proton pump that actively transports protons into the lysosome, ensuring the lysosome maintains its optimal acidic environment. Proper lysosomal pH is necessary for the activity of lysosomal enzymes and for processes like autophagy, where cellular components are broken down and recycled.
TMEM175 and Parkinson’s Disease
Research links the TMEM175 gene to an increased risk of Parkinson’s disease. Mutations or dysfunction of the TMEM175 protein impair lysosomal function. This impairment can lead to an accumulation of cellular waste products, including misfolded proteins like alpha-synuclein.
Alpha-synuclein accumulation is a hallmark characteristic of Parkinson’s disease, forming toxic aggregates known as Lewy bodies in brain cells. When TMEM175 is not functioning correctly, the lysosome’s ability to break down these misfolded proteins is compromised, leading to their buildup and subsequent cellular stress and death, particularly of dopamine-producing neurons in the brain. Studies have shown that TMEM175 deficiency results in unstable lysosomal pH, decreased activity of lysosomal enzymes like glucocerebrosidase, and impaired clearance of autophagosomes, which are structures involved in cellular recycling.
Genetic studies, including genome-wide association studies (GWAS), have identified variants in the TMEM175 gene that are associated with a higher risk of Parkinson’s disease. For instance, the p.M393T variant of TMEM175 has been linked to increased risk, while another variant, p.Q65P, has been shown to reduce disease risk, suggesting a bidirectional effect on disease susceptibility. This indicates that TMEM175 acts as a genetic risk factor, rather than a sole cause, for Parkinson’s disease, contributing to the complex interplay of genetic and environmental factors in its development.
Current Research and Therapeutic Avenues
Ongoing research efforts are focused on further understanding the precise mechanisms by which TMEM175 influences lysosomal function and its connection to Parkinson’s disease. Scientists are investigating how modulating TMEM175 activity could lead to new therapeutic strategies. This includes exploring compounds known as TMEM175 modulators, which are designed to either enhance or inhibit the protein’s function. Positive modulators, or agonists, aim to increase TMEM175 activity, potentially improving lysosomal function and facilitating the degradation of alpha-synuclein aggregates, which could slow or halt disease progression.
The development of selective inhibitors for TMEM175 is also a current area of study, with compounds like 2-phenylpyridin-4-ylamine (2-PPA) and AP-6 being identified as pore blockers that bind to and occlude the ion permeation pathway. These inhibitors are valuable tools for studying TMEM175’s role in lysosomal function and may serve as templates for future drug development. Several companies are actively developing TMEM175 modulators, with some partnering to advance small molecule activators of the protein.
Understanding TMEM175’s role could also lead to new diagnostic tools for Parkinson’s disease, as well as potential therapeutic strategies for other lysosomal storage disorders. Continued investigation into the protein’s structure, function, and its interactions within the cellular environment is paving the way for targeted interventions that could restore cellular balance and address the underlying pathology of Parkinson’s disease.