The PPD (Parkin-PINK1-DJ-1) E3 Ligase Complex and Neurodegeneration

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative movement disorder. No treatment is currently available to prevent disease progression and neurodegeneration, although administration of L-dopa temporarily relieves parkinsonism. Understanding the molecular basis of PD is likely to facilitate development of effective therapies for the disease. We have recently found that proteins encoded by three recessive PD-linked genes, including parkin, PINK1 and DJ-1, form an novel E3 ligase complex to promote ubiquitination and degradation of the parkin substrates, parkin and synphilin-1. Pathogenic parkin and PINK1 mutants show impaired ability to degrade parkin and synphilin-1. Moreover, inactivation of Drosophila PINK1 (dPINKI) using RNAi results in loss of DA neurons and ommatidial degeneration, all of which are rescued by expression of human PINK1 (hPINKI). Furthermore, expression of human SOD1 suppresses neurodegeneration induced bydPINKI inactivation. Treatment of dPINKI RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. These studies demonstrate that dPINKI plays an essential role in maintaining neuronal survival, likely by antagonizing oxidative stress in neurons, and reveal a potential mechanism for neurodegeneration in PD caused by parkin, PINK1 or DJ-1 loss of function. We hypothesize that recessive PD-linked proteins parkin, PINK1 and DJ-1 function coordinately as an E3 ligase complex. Disease-associated mutations should impair E3 ligase activity, resulting in increased susceptibility of DA neurons to oxidative stress. To test this hypothesis, we will: 1. Determine serine/threonine kinase activity of PINK1 in the PPD E3 ligase complex. Hypothesis tested: PINKI's serine/threonine kinase activity plays important roles in regulating PPD E3 ligase activity via phosphorylating components of the PPD complex. 2. Determine reciprocal regulation between PPD E3 activity and oxidative stress. Hypothesis tested: PPD complex prevents cells from undergoing oxidative stress via its E3 ligase activity. Reduced PPD E3 activity leads to increased Oxidative stress. Oxidative stress reciprocally impair PPD E3 complex. 3. Define roles of the PPD complex in neuronal survival. Hypothesis tested: the PPD E3 ligase activity promotes neuronal survival via a mechanism of antagonizing oxidative stress.