Alzheimer's (AD) and the Lewy body diseases (LBD; a family of diseases that includes Parkinson's) are the most common neurodegenerative disorders that appear to be caused by protein deposition. In AD, the amyloid beta peptide (Abeta) forms extracellular deposits, whereas in LBD, alpha-synuclein forms intracellular deposits. While it is clear that familial disease mutations hasten AD or LBD onset by making Abeta or alpha-synuclein more aggregation prone, this only accounts for a minority of AD and LBD cases. Most AD and LBD cases are sporadic (not associated with known mutations), and it is not clear why some individuals develop sporadic; AD or LBD while others do not. Known risk factors, such as hypercholesterolemia and inflammation, suggest a pathogenic mechanism for sporadic AD and LBD. Reactive oxygen species produced during inflammation can convert normal metabolites into aberrant, reactive metabolites, which can, in turn, accelerate AD or LBD onset by covalently modifying Abeta or alpha-synuclein. Preliminary results outlined within demonstrate that aberrant metabolites that possess aldehydes attached to large hydrophobic moieties, can covalently modify Abeta and alpha-synuclein, thus making them more aggregation prone. Herein, experiments are proposed to test the hypothesis that metabolite modification enhances aggregation by Abeta and alpha-synuclein by changing the aggregation mechanism. Techniques involving simple kinetic tests, selective dye binding, fluorescence correlation spectroscopy, and cell-based assays will be employed. Many of these experiments are designed specifically to overcome the technical challenges associated with studying the behavior of Abeta at physiological (nanomolar) concentrations. Characterizing the species and pathways involved in metabolite-initiated protein misfolding could lead to novel therapeutic strategies to target these diseases of growing impact.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050636-03
Application #
7266992
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Murphy, Diane
Project Start
2005-08-03
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$326,094
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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