Parkinson's disease (PD), the second most common neurodegenerative disorder, results from selective loss of midbrain dopamine neurons. Both oxidative stress and intracellular aggregation of proteins, including the protein alpha-synuclein, are implicated in this degeneration. However, the source of oxidative stress, the mechanism of alpha-synuclein deposition, and the relationship between them are unknown. We will examine the role of the neurotransmitter dopamine in generating oxidative stress by manipulating its synthesis, degradation and vesicular transport and measuring production of reactive oxygen species. We will also investigate the effect of dopamine-mediated oxidative stress on alpha-synuclein deposition in model cell culture systems. We will then use this information to determine conditions that promote alpha-synuclein deposition in transgenic mice expressing wild type human alpha-synuclein or a mutant alpha-synuclein that causes an autosomal dominant form of PD. Thus we hope to identify factors that promote oxidative stress in dopamine neurons and to better understand the mechanisms and significance of alpha-synuclein deposition in PD. This work will be conducted under the sponsorship Dr. Robert Edwards in the Departments of Neurology and Physiology at UCSF. Through this work I will learn new techniques in molecular biology, biochemistry and imaging that I will continue to apply to PD. Dr. Edwards and I have developed a training program that includes laboratory research, coursework and didactics that will enable me over the next five years to become an independent investigator concentrating on the neurobiology of PD. In the long term I intend to spend 75% or more of my time dedicated to scientific investigation of PD, and to direct my clinical activities toward patients with PD and other movement disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS002251-05
Application #
6799197
Study Section
NST-2 Subcommittee (NST)
Program Officer
Murphy, Diane
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
5
Fiscal Year
2004
Total Cost
$121,770
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143