Baris Bingol

Institute:Genentech, San Fransisco, USA
Title:PINK1/Parkin/USP30 signaling in Parkinson's Disease
Location:H.R.Kruytgebouw N507
Abstract:["Mitochondrial quality control is central for maintaining a healthy population of mitochondria.\r\nTwo Parkinson's disease genes, mitochondrial kinase PINK1 and ubiquitin ligase Parkin, degrade\r\ndamaged mitochondria though mitophagy. In this pathway, PINK1 senses mitochondrial\r\ndamage and activates Parkin by phosphorylating Parkin and ubiquitin. Activated Parkin then\r\nbuilds ubiquitin chains on damaged mitochondria to tag them for degradation in lysosomes.\r\nUSP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by PINK1 and\r\nParkin. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria\r\nand blocks Parkin\u2019s ability to drive mitophagy, whereas reducing USP30 activity enhances\r\nmitochondrial degradation in neurons. Global ubiquitination site pro\u001fling identi\u001fed\r\nmultiple mitochondrial substrates oppositely regulated by Parkin and USP30. Knockdown of\r\nUSP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves\r\nmitochondrial integrity in Parkin- or PINK1-de\u001fcient \u001eies. Knockdown of USP30 in dopaminergic\r\nneurons protects \u001eies against paraquat toxicity in vivo, ameliorating defects in dopamine\r\nlevels, motor function and organismal survival. Together these data point to a potential\r\nrole for USP30 inhibition in boosting mitochondrial quality control in Parkinson\u2019s Disease."]
Host:Casper Hoogenraad - (0)30 253 4585