Objective/Rationale:
Researchers know that the protein parkin is associated with Parkinson’s disease (PD), but need to know more about its pathways and processes to target it with therapies. The protein endophilin binds to parkin, and parkin levels are elevated in pre-clinical models without endophilin (a technique called knockout). Here, we propose to test the hypothesis that endophilin helps recruit parkin to certain sites on the synapses (structures where neurotransmitter signals pass to other cells). At those sites, Parkin-mediated modulation may regulate protein-protein interactions or control protein levels.
Project Description:
We will first try to answer the question of why parkin levels are higher in endophilin knockout models by determining microRNA level, protein lifetime, synthesis and degradation rate, as well as subcellular localization of parkin in endophilin knockout cells. We will then use biochemical and imaging approaches to investigate the targets of parkin action, its role in the dynamic assembly or degradation of protein complexes and the potential role of endophilin in parkin’s recruitment to the synaptic site.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
While several PD genes have been identified, the precise mechanisms leading to impaired neuronal function in PD are largely unknown. By shedding new light on the function of parkin at the synapse, the proposed study will provide new information toward an improved understanding of mechanisms in neurodegeneration in PD. Our results could also help identify drug targets toward the development of therapeutic strategies to delay the course of PD or to prevent its onset in patients with genetic risk.
Anticipated Outcome:
We expect our studies to provide new insight into mechanisms of PD pathogenesis, with potential implications for therapy.