Numerous age-associated neurodegenerative diseases [e.g., Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), etc.] are associated with aggregation of disease-specific proteins. The finding that the genes encoding these proteins are mutated in some familial forms of these diseases strongly argues that these aggregating proteins cause these diseases. However, for all these diseases the relationship between protein aggregation and cellular pathology has not been clearly established. It is also unknown if the common association of protein aggregation with these diseases reflects a common underlying toxic mechanism, or, alternatively, a common downstream result of cell pathology. We will seek to identify the molecular consequences resulting from the aggregation of three different disease-associated proteins by individually expressing these proteins in a transgenic Caenorhabditis elegans model system. These molecular consequences will be determined by DNA microarray-based gene expression studies and co-immunoprecipitation analyses. Comparison of the molecular responses to expression of different disease-associated proteins will allow identification of common and disease-specific responses. We will then use the molecular genetic tools available in C. elegans to manipulate these molecular responses to determine their role in disease protein toxicity. These studies will directly test whether there is a common underlying toxic mechanism for these neurodegenerative diseases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021037-04
Application #
7076209
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Wise, Bradley C
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2006-07-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$282,267
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Boyd-Kimball, Debra; Poon, H Fai; Lynn, Bert C et al. (2006) Proteomic identification of proteins specifically oxidized in Caenorhabditis elegans expressing human Abeta(1-42): implications for Alzheimer's disease. Neurobiol Aging 27:1239-49
Link, Christopher D (2006) C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimer's disease. Exp Gerontol 41:1007-13
Link, Christopher D; Fonte, Virginia; Hiester, Brian et al. (2006) Conversion of green fluorescent protein into a toxic, aggregation-prone protein by C-terminal addition of a short peptide. J Biol Chem 281:1808-16