Study Rationale: Accumulation of faulty mitochondria (the energy generators of our cells) is thought a be a cause of Parkinson’s disease. Therefore, if we could enhance removal and recycling of these in patients, then it would likely help treat the disease. Through previously funded research, we have found that modulating two pathways (USP7 and ISR) can enhance mitophagy in cells and now we wish to try and stimulate these pathways with drugs in models of Parkinson’s.
Hypothesis: We aim to show that drugs targeting the USP7 or ISR pathways can enhance mitochondrial recycling and in doing so, validate these pathways as therapeutic targets for Parkinson’s disease.
Study Design: We will take candidate drugs that target the USP7 or ISR pathways and treat cells to look at mitochondrial recycling. We will use both biochemical and cell biological approaches to look at this. The next step will be to take the best of these and see if they also work in physiological models of Parkinson’s disease. Together this will allow us to prove that targeting these pathways is therapeutically beneficial and identify candidate drugs for further development.
Impact on Diagnosis/Treatment of Parkinson’s disease: This project has the potential to open new therapeutic approaches to treat Parkinson’s. One set of drugs to be used in this study are already in clinical trials for other diseases. Hence data from this work could greatly speed up progression to new clinical trials for Parkinson’s therapies.
Next Steps for Development: The next steps would be to explore the potential of the ISR molecules in Parkinson’s clinical trials. Likewise for the USP7 pathway drugs, though it is expected more detailed information is needed on how this pathway works, as well as further drug development to ensure correct specificity and targeting to the brain.