Aging increases the risk of neurodegeneration. Strong evidence implicates aggregation-mediated proteotoxicity as the cause of neurodegeneration in numerous clinically important diseases, including Alzheimer's disease, although the etiology is unclear. Emerging genetic data suggest that the aging process is linked by signaling pathways to the fidelity of protein homeostasis, including the ability to recover or dispose of misfolded or aggregated proteins. Overall this program project strives to meet two goals: 1) to understand the organismal, cell biological and molecular bases for the pathways that protect organisms from protein aggregation, and 2) to determine how these pathways become compromised as an organism ages. The Kelly Laboratory will focus on the biochemical characterization of the pathway(s) and the underlying molecular determinants of the disaggregase activity that appears to protect against age onset proteotoxicity in C. elegans and murine models of Alzheimer's and in human cells and they will test the hypothesis that amyloidogenesis is a constitutive process. The Balch Laboratory will generate senescence cell models to probe the role of age-dependent changes in exocytic and endocytic APR and Abeta processing that appear to contribute to proteotoxicity and will employ their expertise to perturb the exocytic and endocytic pathways to understand the genesis of Abeta proteotoxicity. The Dillin Laboratory will utilize genetic, proteomic and bioinformatics approaches and animal models of Alzheimer's disease to understand how and which aging-associated signaling pathways and downstream determinants affect proteotoxicity and they will carry out Abeta aggregate structure toxicity assessments in the worm Alzheimer's model. The bioinformatics, proteomics and neurosciences and neuropathology cores are each intimately associated with two or more of these projects that are themselves highly interdependent. The results obtained from this project will not only provide insight into the relationship between aging and neurodegeneration, but should provide the information necessary to develop therapeutic strategies for age-associated neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG031097-04
Application #
8215836
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8 (O4))
Program Officer
Refolo, Lorenzo
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-03-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$1,956,487
Indirect Cost
$607,685
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego et al. (2015) ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 528:510-6
Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward et al. (2015) Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease. Neurobiol Dis 74:144-57
Park, Sung Kyu Robin; Aslanian, Aaron; McClatchy, Daniel B et al. (2014) Census 2: isobaric labeling data analysis. Bioinformatics 30:2208-9
Greiner, Erin R; Kelly, Jeffery W; Palhano, Fernando L (2014) Immunoprecipitation of amyloid fibrils by the use of an antibody that recognizes a generic epitope common to amyloid fibrils. PLoS One 9:e105433
Koob, Andrew O; Shaked, Gideon M; Bender, Andreas et al. (2014) Neurogranin binds α-synuclein in the human superior temporal cortex and interaction is decreased in Parkinson's disease. Brain Res 1591:102-10
Bamberger, Casimir; Pankow, Sandra; Park, Sung Kyu Robin et al. (2014) Interference-free proteome quantification with MS/MS-based isobaric isotopologue detection. J Proteome Res 13:1494-501
Tsigelny, Igor F; Sharikov, Yuriy; Kouznetsova, Valentina L et al. (2014) Structural diversity of Alzheimer's disease amyloid-β dimers and their role in oligomerization and fibril formation. J Alzheimers Dis 39:583-600
Roth, Daniela Martino; Hutt, Darren M; Tong, Jiansong et al. (2014) Modulation of the maladaptive stress response to manage diseases of protein folding. PLoS Biol 12:e1001998
Alvarez, Antón; Aleixandre, Manuel; Linares, Carlos et al. (2014) Apathy and APOE4 are associated with reduced BDNF levels in Alzheimer's disease. J Alzheimers Dis 42:1347-55
Baird, Nathan A; Douglas, Peter M; Simic, Milos S et al. (2014) HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. Science 346:360-3

Showing the most recent 10 out of 55 publications