Study Rationale: Preserving the fidelity of genetic information is essential for life. Consequently, all organisms have developed efficient systems for repairing DNA damage. One of the consequences of derangement in these mechanisms is aging, which is a major risk factor for Parkinson’s disease (PD). However, our understanding of the role of DNA damage and repair in PD is rudimentary. Our analysis of the PPMI cohort has shown that derangement of DNA repair mechanisms can predict progression of PD motor symptoms. This study would provide additional important evidence at the level of cell biology.
Hypothesis: We hypothesize that neurons obtained from reprogrammed skin cells of people with PD will display impaired DNA repair and that the magnitude of this defect will reflect disease severity.
Study Design: We will use cell biology technologies to transform skin cells obtained from people with PD into neurons. We will then treat these cells with compounds that induce different types of DNA and evaluate the cells’ ability to repair this disruption using microscopy and DNA sequencing techniques. Lastly, we will correlate these biological parameters with clinical measures of disease severity to determine whether DNA damage predicts disease progression.
Impact on Diagnosis/Treatment of Parkinson’s disease: The project could improve PD diagnosis and the prediction of disease progression, which would allow more judicious therapeutic planning. It would enhance understanding of PD mechanisms by incorporating age-related DNA damage into experimental models. It would also facilitate development of therapeutics that enhance DNA repair, for instance via metabolic interventions.
Next Steps for Development: The next step would be the development of a prototype pipeline and its independent validation in an operational environment, that is a hospital.