As humans live longer, age-related neurodegenerative disorders caused by the accumulation of abnormal proteins are becoming increasingly common. In all cells, a protein quality control network (PQC) exists to "handle" such abnormal proteins arising from mutations, environmental stressors or the aging process. The selective brain vulnerability in age-related neurodegenerative disorders, however, suggests there is something unique about PQC in the brain that makes this organ particularly susceptible to misfolded proteins. Unfortunately, which PQC components are most important in the brain and how these components respond when exposed to abnormal proteins remain unknown. The studies proposed here will systematically explore changes in PQC that occur when aggregation-prone proteins are expressed in brain and will define mechanistically how a key PQC ubiquitin ligase, CHIP, handles neurodegenerative disease proteins. The underlying hypothesis is twofold: 1) PQC in the brain fails to keep pace with mounting proteotoxic stress during age-related neurodegeneration;and 2) the brain's PQC response to proteotoxic stress relies heavily on CHIP, a multifunctional protein that mediates crosstalk between chaperone- and ubiquitin-dependent pathways. In three Aims that build off the investigators'expertise in polyglutamine neurodegeneration and ubiquitin ligase biology, we will use complementary genetic and biochemical techniques to map basal and adaptive PQC changes in the aging mouse brain and in mouse models of polyglutamine neurodegenerative disease, both in the presence and absence of CHIP. Additional studies will determine the mechanisms by which CHIP ligase complexes are regulated in brain. The proposed studies will identify key PQC components that act on abnormally folded protein in the CNS and provide insights into their mechanisms of action. The results are expected to suggest targets for therapeutic strategies in a wide range of age-related neurodegenerative disorders.

Public Health Relevance

Many common, incurable brain diseases that develop as people get older are associated with abnormal protein deposits in the brain. This proposal seeks to understand and define the quality control machinery inside brain cells that counteracts these abnormal proteins. Understanding this machinery may suggest routes to therapy for a large range of sporadic and hereditary neurodegenerative diseases that occur as we age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034228-04
Application #
8308421
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Wise, Bradley C
Project Start
2009-09-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$293,957
Indirect Cost
$98,881
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Atkin, Graham; Hunt, Jack; Minakawa, Eiko et al. (2014) F-box only protein 2 (Fbxo2) regulates amyloid precursor protein levels and processing. J Biol Chem 289:7038-48
Smith, Matthew C; Scaglione, K Matthew; Assimon, Victoria A et al. (2013) The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry 52:5354-64
Todd, Peter K; Oh, Seok Yoon; Krans, Amy et al. (2013) CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78:440-55
Scaglione, Kenneth Matthew; Basrur, Venkatesha; Ashraf, Naila S et al. (2013) The ubiquitin-conjugating enzyme (E2) Ube2w ubiquitinates the N terminus of substrates. J Biol Chem 288:18784-8
Scaglione, K Matthew; Zavodszky, Eszter; Todi, Sokol V et al. (2011) Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP. Mol Cell 43:599-612