Title : Neurodegereration, aging & mitochondria
Abstract:
Mutations in PINK1 and PARKIN lead to inherited forms of Parkinson’s Disease (PD). My lab was one of the first to report the
function of the PINK1 gene, and to show that PINK1 and parkin function in a common pathway to regulate mitochondrial integrity and quality. Mitochondrial morphology (dynamics) is controlled by two opposing actions, mitochondrial fusion, which is regulated by mitofusin, and mitochondria fission, which is controlled by drp1. We discovered that the PINK1/parkin pathway degrades mitofusin (inhibits mitochondrial fusion), and promotes Drp1 (mitochondrial fission). Our work provided compelling evidence that mitochondrial dysfunction underlies PD pathogenesis. In addition to mitofusin and Drp1, we have identified multiple other regulators of mitochondrial health that interact with PINK1/parkin in PD models. These include MUL1 (degrades Mitofusin in parallel of the PINK1/parkin pathway), VCP (degrades Mitofusin), atg1 (increases Drp1 in addition to promoting autophagy) and clueless/CluH (a new regulator of Drp1). We have also developed the first transgenic model of mitochondrial DNA (mtDNA) heteroplasmy related to cellular aging and have identified factors that allow us to remove up to 95% damaged mtDNA. These genes and pathways may serve as therapeutic targets for PD and have the potential to reverse aging.
