Parkinson?s disease (PD) is a devastating neurological disorder that afflicts over 1 million North Americans and is characterized by gait difficulty, rigidity, and tremor. Although symptomatic therapies are effective in the early stages of PD, no treatments exist to alter the inexorable progression of the disorder. The recent identification of two genes that underlie familial inherited forms of PD, alpha-Synuclein (alpha-Syn) and Parkin, has afforded new clues regarding the molecular pathogenesis of PD. Interestingly, aggregates of alpha-Syn protein, along with ubiquitin, a protein degradation marker, appear to be major constituents of the intracytoplasmic inclusions that typify PD, termed Lewy bodies. Furthermore, the primary structure of Parkin displays sequence homology to ubiquitin ligases, implicating it directly in the ubiquitin/proteasome pathway. Thus, Parkin and alpha-Syn are both implicated in a common potential mechanism of PD pathology: abnormal protein processing and degradation. The analysis of alpha-Syn deficient animals suggests a role for alpha-Syn in the regulation of dopamine release at central synaptic terminals, but it remains unclear how this relates to the pathological activity of mutations in this gene. I intend to utilize complementary mouse genetic, cellular, and biochemical techniques to investigate the mechanisms of action of Parkin and alpha-Syn. Specifically, I propose to test the hypothesis that these genes play roles in common genetic and biochemical pathways in familial PD. By gaining insight into the normal and pathological functions of these genes, it may be possible to develop disease-altering therapies for PD in the foreseeable future. Questions that will be investigated include: --How do alpha-Syn and Parkin mutations cause dopamine neuron loss? --Do mutations in alpha-Syn and Parkin act within a common genetic pathway? --How do the normal activities of these proteins relate to their pathological functions?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS043744-02
Application #
6604885
Study Section
Special Emphasis Panel (ZNS1-SRB-K (03))
Program Officer
Murphy, Diane
Project Start
2002-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$205,461
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