Loss-of-function mutations in parkin cause approximately 50% of cases of early-onset Parkinson's disease (PD). Parkin selectively targets impaired mitochondria (powerhouses of the cell) for degradation (break down). Recent structural studies of parkin have revealed that this protein exists in an auto-inhibited (shut "off") state. This detailed structural knowledge has enabled the generation of parkin genetic variants, such as W403A, that activate parkin and promote Parkin E3 ubiquitin ligase (regulates parkin activity) in cell-based and cell-free assays (analytic tests).
We hypothesize that W403A pre-clinical models will have increased Parkin E3 ligase activity, which may be neuroprotective, since overexpression of wild-type parkin protects dopamine neurons.
In anticipation of clinical trials to test the safety and efficacy of parkin-activating compounds, W403A pre-clinical models should be tested for on-target activation of endogenous parkin. As a first step, we will measure the activity of parkin in W403A pre-clinical models to validate the effects of the parkin W403A mutation.
Impact on Diagnosis/Treatment of Parkinson's Disease:
This project will facilitate the development and testing of novel treatments for PD based on activating parkin.
Next Steps for Development:
The tools developed during this project may be useful as outcome measures for clinical trials of treatments designed to activate parkin.