Study Rationale: Evidence is accumulating that the Parkin and PINK1, gene products whose activities are altered in Parkinson’s disease (PD), play a role in immune signaling. We previously identified a pathway that links the neuroprotective and immune functions of Parkin via an unconventional mode of modification that involves the tagging of target proteins with a linear chain of ubiquitin. Our most recent work revealed that PINK1 regulates this “linear ubiquitination” pathway by adding a phosphate group to linear ubiquitin chains.
Hypothesis: We hypothesize that PINK1 stabilizes innate immune signaling complexes at mitochondria, thereby protecting neurons from cell death.
Study Design: We will use various cellular models to study the stabilization and function of PINK1 at mitochondria in immune-signaling paradigms. This approach will allow us to establish a potential causal link between innate immune signaling and the maintenance of cell viability that may contribute to the neuroprotective function of PINK1.
Impact on Diagnosis/Treatment of Parkinson’s disease: We expect that this project will reveal a new function for PINK1, which is normally rapidly degraded inside cells. Identifying conditions under which mature PINK1 accumulates and elucidating its neuroprotective functions will enhance our understanding of the pathogenic mechanisms of PD and may reveal novel targets for innovative therapeutic approaches.
Next Steps for Development: Next steps include the validation of our findings in cells derived from people with PD, such as neuronal cells produced from iPS cells. We should, in addition, be able to screen for conditions and small molecules that stabilize mature PINK1.