Defective protein degradation through the ubiquitin proteasome pathway (UPP) has been hypothesized to play a central role in neurodegenerative disorders such as Parkinson's disease (PD). Mutations in Parkin, a putative ubiquitin ligase component, cause a familial, autosomal recessive form of PD characterized by midbrain dopamine neuron loss. It has therefore been hypothesized that inefficient degradation and consequent toxic accumulation of Parkin ubiquitination substrates underlie the loss of dopamine neurons in autosomal recessive Parkinson's disease. We further hypothesize that Parkin may play a direct role in regulating neuronal survival in the CNS. We propose to use molecular and cellular tools to investigate the mechanism of Parkin action in protein ubiquitination and neuronal survival. Our preliminary data indicate that Parkin associates in a multiprotein ubiquitin ligase complex with 2 previously characterized ubiquitin ligase components, the F-box/WD repeat-containing protein hSel- 10, and Cullin-1 (Cul 1). Furthermore, hSel-10 serves to direct this complex to specific substrates including Cyclin E, a putative regulator of neuronal apoptosis. We will test the hypotheses that (1) auxiliary components of the Parkin ubiquitin ligase complex serve to regulate or target this activity, and (2) that, in Parkin-associated familial PD, premature neuronal death is a consequence of defective ubiquitination and the accumulation of neuronal apoptosis-related Parkin complex substrates. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046659-04
Application #
7084412
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Murphy, Diane
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$379,188
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032