The aggregation/fibrillation of alpha-synuclein is a critical factor in Parkinson's disease (PD). Alpha-Synuclein is a significant component of intracellular inclusions known as Lewy bodies that are the pathological hallmark of PD and mutations and gene triplication of alpha-synuclein have been associated with rare cases of familial PD. Our overall goals are to design molecules that will inhibit alpha-synuclein aggregation, and disaggregate existing alpha-synuclein fibrils. There is a critical need for an effective treatment of Parkinson's disease, since current therapies are only partially effective in treating the symptoms. Our preliminary data indicate that some catechols, flavonoids and related compounds have the potential to inhibit fibrillation of alpha-synuclein and disaggregate existing fibrils.
The aims of this proposal are: 1) To determine the underlying molecular mechanisms of the inhibition of alpha-synuclein fibrillation by catechols, flavonoids and related compounds. Our preliminary investigations suggest that it is an oxidized form of the catechol that is most effective in inhibiting fibrillation. 2) To identify the active species, and the mechanism of disaggregation of alpha-synuclein fibrils by catechol-type compounds. 3) To determine whether catechols and related compounds prevent alpha-synuclein fibrillation and disaggregate fibrils in vivo. We will also perform a systematic investigation of the most promising compounds (as inhibitors and """"""""disaggregators"""""""") to identify key structural features in order to identify additional molecules that might be more suited for potential therapeutic uses. The results of the proposed research should provide leads for inhibitors of alpha-synuclein aggregation and lay the groundwork for potential therapeutic approaches. In the long-run this research could provide new strategies for the treatment of Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048584-02
Application #
7071893
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Murphy, Diane
Project Start
2005-06-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$278,751
Indirect Cost
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064