A single mutation in a gene called PINK1 can cause hereditary Parkinson's disease, and researchers now want to understand exactly how that happens at the molecular level. The problem is that while scientists know PINK1 mutations lead to Parkinson's, the chain of events inside cells remains unclear. This lab has already discovered that PINK1 activates another protein, Parkin, by adding a phosphate group to it, which then triggers Parkin to tag damaged mitochondria for removal. This project will answer how PINK1 itself gets switched on, whether this pathway is broken in patients with sporadic (non-hereditary) Parkinson's, and what other proteins PINK1 and Parkin act upon. This is fundamental science. It will not produce a treatment next year. But understanding the precise molecular machinery that goes wrong in Parkinson's could eventually lead to diagnostic tests that detect the disease earlier, or drugs that restore the pathway. Similar fundamental discoveries about protein misfolding in Alzheimer's, for example, opened entirely new avenues for drug development that are now in clinical trials.
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Mutations in PTEN-induced kinase 1 (PINK1) cause hereditary Parkinson's disease (PD). Understanding how PINK1 mutations lead to PD remains a major question in the PD field. During the last 4 years, my laboratory has made a series of significant advances that have shed light on the regulation and function of the PINK1 kinase. I have found that PINK1 is activated following mitochondrial membrane potential depolarization and that it phosphorylates another PD-linked protein, the RING E3 ligase Parki n, at Serine 65. This leads to activation of Parkin E3 ligase activity. This proposal is aimed at addressing key questions that arise from these findings. I will investigate the mechanism by which PINK1 becomes activated by mitochondrial depolarization. I will utilize highly sensitive monoclonal phospho-specific antibodies to determine whether the PINK1-Parkin pathway is disrupted in patients with sporadic PD. I will investigate the physiological role of the PINK1-Parkin pathway in vivo by ch aracterizing a Parkin Ser65Ala knock-in mouse and determine whether this leads to neurodegeneration or mitochondrial defects. I will employ state-of-the-art mass spectrometry technologies to search for physiological substrate(s) of Parkin whose ubiquitylation is dependent on Parkin phosphorylation at Serine 65 in these mice. I will investigate the function of newly discovered PINK1 substrates, Rab 8a/b and Rab 13. I will elucidate the crystal structure of PINK1. Greater understanding of the role of the PINK1-Parkin pathway in PD may lead to new insights to diagnose, monitor and treat the underlying disease process.
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