A hallmark of most neurodegenerative diseases is the accumulation of toxic, misfolded proteins. A better understanding of how protein fate determination occurs may reveal novel therapeutic targets for degenerative brain diseases. While much has been learned about how the protein quality control system of neurons handles abnormal proteins, a major unresolved question remains: How is the determination to fold or degrade such proteins made by the chaperone and ubiquitin systems? The proposed studies will test the overall hypothesis that a specific E2 enzyme, Ube2w, regulates protein fate by rapidly monoubiquitinating misfolded proteins.
Aim 1 will employ Ube2w knockout mice and a mouse model of tauopathy to investigate Ube2w's predicted neuroprotective role in vivo.
Aim 2 will define the novel mechanism by which Ube2w rapidly attaches ubiquitin to substrates.
Aim 3 will seek to establish a direct correlation between the unfoldedness of a substrate protein and the attachment of ubiquitin by Ube2w and other E2s. Together these aims will help elucidate the role of Ube2w in degrading proteotoxic proteins and may provide insight into its role in countering neurotoxicity.

Public Health Relevance

The work proposed here will advance our understanding of how the ubiquitin and the chaperone systems collaborate to determine the fate of misfolded proteins. The work performed here may lead to novel drug targets and increase our understanding of how basic cellular pathways function to protect neurons from proteotoxic species.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Career Transition Award (K99)
Project #
5K99NS073936-02
Application #
8489365
Study Section
NST-2 Subcommittee (NST)
Program Officer
Sutherland, Margaret L
Project Start
2012-07-01
Project End
2013-07-31
Budget Start
2013-07-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$98,679
Indirect Cost
$7,310
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
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
Tsou, Wei-Ling; Burr, Aaron A; Ouyang, Michelle et al. (2013) Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo. J Biol Chem 288:34460-9
Blair, Laura J; Nordhues, Bryce A; Hill, Shannon E et al. (2013) Accelerated neurodegeneration through chaperone-mediated oligomerization of tau. J Clin Invest 123:4158-69
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
Faggiano, Serena; Menon, Rajesh P; Kelly, Geoff P et al. (2013) Enzymatic production of mono-ubiquitinated proteins for structural studies: The example of the Josephin domain of ataxin-3. FEBS Open Bio 3:453-8