Parkinson’s disease is a progressive disorder of movement and coordination due to the specific loss of dopaminergic neurons in the brain. There are no medicines that can slow or halt the disease process largely due to lack of understanding of the fundamental mechanisms. Spectacular advances in genetics have identified nearly 20 genes that are mutated in familial forms of the disease. Understanding the regulation and signaling networks in which these genes reside is likely to elaborate new knowledge on the key cellular pathways that are vital for maintaining neuronal integrity and health. It may also lead to the development of novel approaches to better diagnose and treat Parkinson’s.
My lab studies the protein kinase, PTEN-induced kinase 1 (PINK1) in which loss of function mutations lead to Parkinson’s. Multiple lines of evidence indicate that PINK1 is a master regulator of a mitochondrial damage response pathway that exists in many different cell types including neurons. Under healthy conditions PINK1 is inactive, however, upon selective mitochondrial stress, PINK1 is activated and stimulates the removal of damaged mitochondrial via autophagy (termed mitophagy) thereby promoting cell survival.
We have discovered the key downstream substrates of PINK1 including the RBR E3 ligase, Parkin, and ubiquitin and elucidated the mechanism of activation of Parkin E3 ligase activity by phosphorylated-ubiquitin. To date PINK1 is the only known ubiquitin kinase and we have a major interest in understanding this interplay between phosphorylation and ubiquitin to signaling mechanisms. More recently we have uncovered a new PINK1-dependent regulation of Rab GTPases whose functional link to Parkinson’s disease remains to be solved.