Parkinson's Disease (PD) is a neurodegenerative disorder associated with selective and progressive death of dopaminergic neurons. Although the cause of death for these neurons is not known, hereditary forms of PD have provided clues. The most frequently mutated gene in autosomal recessive juvenile Parkinsonism (AR-JP) is PARK2, which encodes parkin. Parkin-null mice do not develop PD during their lifespan, but their brains show defects in mitochondrial and antioxidant functions. This and other observations have led to the proposal that death of dopaminergic neurons in human PD is a result of inability to cope with oxidative stress due to mitochondrial and antioxidant dysfunction. Our work with SCFCdc4/Fbw7 has suggested a functional link between this protein-ubiquitin ligase and parkin. Preliminary data suggest that parkin, itself a ubiquitin ligase, targets Cdc4/Fbw7, the rate- limiting component of SCFCdc4/Fbw7, for ubiquitin-mediated destruction. The current proposal explores the potential links between stabilization of Cdc4/Fbw7 in parkin-mutated neurons and the phenotypes associated with parkin mutation, particularly in the context of an SCFCdc4/Fbw7 substrate, the transcriptional co-activator PGC-1. PGC-1 controls mitochondrial and antioxidant function in the brain, and therefore SCFCdc4-dependent PGC-1 downregulation in parkin-mutated brains could account for most if not all of the known parkin-null phenotypes.

Public Health Relevance

Parkinson's disease and related syndromes constitute a set of devastating neurodegenerative disorders. Most inherited Parkinson's disease is characterized by mutations in the PARK2 gene. The current proposal seeks to determine the function of parkin, encoded by the PARK2 gene, in the hope of developing new therapeutic approaches to Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059904-03
Application #
8054203
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sutherland, Margaret L
Project Start
2009-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$372,204
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Ekholm-Reed, Susanna; Goldberg, Matthew S; Schlossmacher, Michael G et al. (2013) Parkin-dependent degradation of the F-box protein Fbw7? promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol 33:3627-43