Study Rationale:
Parkinson’s disease develops through a combination of ageing, environmental factors, and genetic risk. One gene linked to Parkinson’s is TMEM175, which encodes an ion channel that helps lysosomes — the cell’s recycling centres — function properly. Lysosomes are essential for breaking down waste and preventing the accumulation of toxic proteins such as alpha-synuclein. Genetic changes in TMEM175 have been shown to alter Parkinson’s disease risk, but for most variants found in patients, we do not know whether they disrupt channel function or are harmless. This lack of functional information limits genetic diagnosis and slows the development of therapies that target lysosomal pathways.
Hypothesis:
We hypothesize that different genetic variants in TMEM175 have distinct effects on ion channel activity, and that reduced or altered activity contributes to lysosomal dysfunction and Parkinson’s disease risk.
Study Design:
We will systematically test how single-amino-acid variants in TMEM175 affect channel function in human cells. Thousands of variants will be introduced into cells using a pooled approach, and their activity will be measured in parallel using a fluorescence-based assay that reports ion flow through the channel. In parallel, we will measure the abundance of each variant using an antibody-based readout. For selected variants, we will confirm results using detailed electrical measurements and cell imaging. This approach will generate a comprehensive map showing how each TMEM175 variant affects both activity and abundance.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This project will help distinguish harmful TMEM175 variants from benign ones, improving interpretation of genetic test results. It will also identify variants that increase or decrease channel activity, providing insights that can guide the development of drugs targeting TMEM175 and lysosomal dysfunction in Parkinson’s disease.
Next Steps for Development:
The variant map will be shared openly with clinicians and researchers and used to prioritize TMEM175 variants for further study in patient-derived cells and animal models. These results will support future efforts to develop and test therapies that restore lysosomal function in Parkinson’s disease.