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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Wise, Bradley C
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Wang, Bo; Zeng, Li; Merillat, Sean A et al. (2018) The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin. Neurobiol Dis 109:127-136
Wang, Bo; Merillat, Sean A; Vincent, Michael et al. (2016) Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems. J Biol Chem 291:3030-42
Atkin, Graham; Moore, Shannon; Lu, Yuan et al. (2015) Loss of F-box only protein 2 (Fbxo2) disrupts levels and localization of select NMDA receptor subunits, and promotes aberrant synaptic connectivity. J Neurosci 35:6165-78
Zeng, Li; Wang, Bo; Merillat, Sean A et al. (2015) Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3. Neurobiol Dis 82:281-288
Tallaksen-Greene, Sara J; Sadagurski, Marianna; Zeng, Li et al. (2014) Differential effects of delayed aging on phenotype and striatal pathology in a murine model of Huntington disease. J Neurosci 34:15658-68
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
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
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
Ashizawa, Tetsuo; Figueroa, Karla P; Perlman, Susan L et al. (2013) Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis 8:177
Todd, Peter K; Paulson, Henry L (2013) C9orf72-associated FTD/ALS: when less is more. Neuron 80:257-8

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