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.
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.
|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|
|Vittal, Vinayak; Shi, Lei; Wenzel, Dawn M et al. (2015) Intrinsic disorder drives N-terminal ubiquitination by Ube2w. Nat Chem Biol 11:83-9|
|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|
|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|
|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|
|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|
|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|
|Thompson, Andrea D; Scaglione, K Matthew; Prensner, John et al. (2012) Analysis of the tau-associated proteome reveals that exchange of Hsp70 for Hsp90 is involved in tau degradation. ACS Chem Biol 7:1677-86|