Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A

• Type of Material: Article
• Authors: Kavita P. Bhat, Emory University; Sen Yan, Emory University; Chuanen Wang, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Language: English
• Date: 2014-04-15
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2020 National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1402215111
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 111
• Issue: 15
• Start Page: 5706
• End Page: 5711
• Grant/Funding Information: This work was supported by National Institutes of Health Grants AG19206(to X.J.L.); NS041449 (to X.J.L.); AG031153 (to S.H.L.); and NS0405016 (to S.H.L.).
• Keywords: POLYGLUTAMINE PROTEIN; PROTEASOMAL DEGRADATION; DISEASE; misfolding; MUTANT HUNTINGTIN; NUCLEAR-LOCALIZATION; TRANSGENIC MICE; Science & Technology - Other Topics; NEURONAL INTRANUCLEAR INCLUSIONS; proteolysis; Multidisciplinary Sciences; Science & Technology; MOUSE MODEL; ANGELMAN SYNDROME; MOLECULAR PATHOGENESIS
• Research Categories: Biology, Molecular; Biology, Genetics

Abstract

Ubiquitination of misfolded proteins, a common feature of many neurodegenerative diseases, is mediated by different lysine (K) residues in ubiquitin and alters the levels of toxic proteins. In Huntington disease, polyglutamine expansion causes N-terminal huntingtin (Htt) to misfold, inducing neurodegeneration. Here we report that shorter N-terminal Htt fragments are more stable than longer fragments and find differential ubiquitination via K63 of ubiquitin. Aging decreases proteasome-mediated Htt degradation, at the same time increasing K63-mediated ubiquitination and subsequent Htt aggregation in HD knock-in mice. The association of Htt with the K48-specific E3 ligase, Ube3a, is decreased in aged mouse brain. Overexpression of Ube3a in HD mouse brain reduces K63-mediated ubiquitination and Htt aggregation, enhancing its degradation via the K48 ubiquitin-proteasome system. Our findings suggest that aging-dependent Ube3a levels result in differential ubiquitination and degradation of Htt fragments, thereby contributing to the age-related neurotoxicity of mutant Htt.