Study Rationale: Parkinson’s disease (PD) is associated with loss of dopamine neurons and aggregation of the protein alpha-synuclein. Mutations that impair the function of PINK1 and PRKN, proteins involved in cellular quality control processes, cause familial forms of PD. Understanding how the activity of PINK1 and PRKN in specific cell types changes in response to stress, and how cells’ stress response is altered in the absence of PINK1 and PRKN, will be critical for uncovering the mechanisms and cell types that contribute to neuronal loss.
Hypothesis: We hypothesize that pre-formed fibrils of alpha-synuclein will induce cell type-specific changes in PINK1 and PRKN expression and that the cells’ stress response will be altered in the absence of PINK1 and/or PRKN.
Study Design: Using spatial transcriptomics — techniques for monitoring the genes active in different cells — we will catalog the cell type-specific responses to stress induced by pre-formed fibrils of alpha-synuclein and determine how loss of PINK1 and PRKN affect this response in the brains of rats. We will also assess the effects of regional and cell-type specific activation of the PINK1/PRKN pathway using a variety of histological and biochemical approaches. Lastly, we will apply these same methods to postmortem human brain tissue to cross-validate our findings in people with PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: These studies will be instrumental in uncovering mechanisms important for dopamine neuron vulnerability or neuroprotection and in characterizing which cell types contribute to neuronal loss in the absence of PINK1 and PRKN function.
Next Steps for Development: The mechanisms and cell types identified through these studies will serve as potential therapeutic targets for future studies.