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.
|Kanack, Adam J; Newsom, Oliver J; Scaglione, Kenneth Matthew (2018) Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP. J Biol Chem 293:2735-2743|
|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|
|Sutton, Joanna R; Blount, Jessica R; Libohova, Kozeta et al. (2017) Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3. Hum Mol Genet 26:1419-1431|
|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|
|Ristic, Gorica; Tsou, Wei-Ling; Guzi, Ermal et al. (2016) USP5 Is Dispensable for Monoubiquitin Maintenance in Drosophila. J Biol Chem 291:9161-72|
|Vittal, Vinayak; Shi, Lei; Wenzel, Dawn M et al. (2015) Intrinsic disorder drives N-terminal ubiquitination by Ube2w. Nat Chem Biol 11:83-9|
|Santarriaga, Stephanie; Petersen, Amber; Ndukwe, Kelechi et al. (2015) The Social Amoeba Dictyostelium discoideum Is Highly Resistant to Polyglutamine Aggregation. J Biol Chem 290:25571-8|
|Faggiano, Serena; Menon, Rajesh P; Kelly, Geoff P et al. (2015) Allosteric regulation of deubiquitylase activity through ubiquitination. Front Mol Biosci 2:2|
|Zhang, Huaqun; Amick, Joseph; Chakravarti, Ritu et al. (2015) A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins. Structure 23:472-482|
|Blount, Jessica R; Tsou, Wei-Ling; Ristic, Gorica et al. (2014) Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun 5:4638|
Showing the most recent 10 out of 17 publications