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

• Authors: Kavita P. Bhat, Emory University; Sen Yan, Emory University; Chuanen Wang, Emory University; Shihua Li, Emory University; Xiao-Jiang Li, Emory University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 111, Number 15
• Publisher: National Academy of Sciences | 2014-04-15, Pages 5706-5711
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.1402215111
• Subjects: Biology, Molecular; Biology, Genetics
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; misfolding; proteolysis; NEURONAL INTRANUCLEAR INCLUSIONS; MUTANT HUNTINGTIN; PROTEASOMAL DEGRADATION; MOLECULAR PATHOGENESIS; POLYGLUTAMINE PROTEIN; NUCLEAR-LOCALIZATION; ANGELMAN SYNDROME; TRANSGENIC MICE; MOUSE MODEL; DISEASE

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.