Study Rationale:
Our aim is to develop a drug that will slow or stop the progression of Parkinson’s disease in patients who carry a mutation in the TMEM175 gene. The TMEM175 gene produces a protein that helps lysosomes — tiny structures inside cells — recycle damaged components within the cell. Mutations in TMEM175 compromise its normal activity, impair recycling and are significant risk factors for Parkinson’s disease development and earlier age-of-onset.
Hypothesis:
Our hypothesis is that increasing TMEM175 activity will enhance the efficiency of cellular recycling processes, leading to breakdown of toxic fats and protein clumps found in brain cells of Parkinson’s patients.
Study Design:
First, we will use engineered cells containing TMEM175 mutations to assess how protein dysfunction may contribute to disease. Second, we will test hundreds of thousands of possible drugs to determine whether any of them is capable of increasing TMEM175 activity. Finally, we will test whether any drugs that do restore TMEM175 activity could benefit Parkinson’s patients by testing them in cultured neurons.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our goal is a drug which augments TMEM175 activity and slows or stops the progression of Parkinson’s disease in patients who carry a mutation in the TMEM175 gene.
Next Steps for Development:
If this project is successful, we will apply modern drug discovery techniques to improve our drugs, making them as effective as possible while ensuring they are safe for long-term use, before starting clinical trials.