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 #
5R01NS050636-02
Application #
7105552
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
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$335,833
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Liu, Yu; Tan, Yun Lei; Zhang, Xin et al. (2014) Small molecule probes to quantify the functional fraction of a specific protein in a cell with minimal folding equilibrium shifts. Proc Natl Acad Sci U S A 111:4449-54
Zhang, Xin; Liu, Yu; Genereux, Joseph C et al. (2014) Heat-shock response transcriptional program enables high-yield and high-quality recombinant protein production in Escherichia coli. ACS Chem Biol 9:1945-9
Palhano, Fernando L; Lee, Jiyong; Grimster, Neil P et al. (2013) Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils. J Am Chem Soc 135:7503-10
Talantova, Maria; Sanz-Blasco, Sara; Zhang, Xiaofei et al. (2013) A? induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 110:E2518-27
Lee, Jiyong; Culyba, Elizabeth K; Powers, Evan T et al. (2011) Amyloid-? forms fibrils by nucleated conformational conversion of oligomers. Nat Chem Biol 7:602-9
Usui, Kenji; Hulleman, John D; Paulsson, Johan F et al. (2009) Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity. Proc Natl Acad Sci U S A 106:18563-8
Bieschke, Jan; Siegel, Sarah J; Fu, Yanwen et al. (2008) Alzheimer's Abeta peptides containing an isostructural backbone mutation afford distinct aggregate morphologies but analogous cytotoxicity. Evidence for a common low-abundance toxic structure(s)? Biochemistry 47:50-9
Balch, William E; Morimoto, Richard I; Dillin, Andrew et al. (2008) Adapting proteostasis for disease intervention. Science 319:916-9
Powers, Evan T; Powers, David L (2008) Mechanisms of protein fibril formation: nucleated polymerization with competing off-pathway aggregation. Biophys J 94:379-91
Stewart, Cameron R; Wilson, Leanne M; Zhang, Qinghai et al. (2007) Oxidized cholesterol metabolites found in human atherosclerotic lesions promote apolipoprotein C-II amyloid fibril formation. Biochemistry 46:5552-61

Showing the most recent 10 out of 13 publications