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Author Notes:

Xiao-Jiang Li: xli2@emory.edu

K.P.B., S.L., and X.-J.L. designed research; K.P.B., S.Y., and C.-E.W. performed research; S.Y. and C.-E.W. contributed new reagents/analytic tools; K.P.B., S.L., and X.-J.L. analyzed data; and K.P.B. and X.-J.L. wrote the paper.

We thank Dr. Kah-Leong Lim (Department of Biological Sciences, National University of Singapore) for providing myc-tagged WT-ubiquitin, K48, K48R, K63, and K63R ubiquitin lysine mutant constructs; and Cheryl Strauss for critical reading of this manuscript.

The authors declare no conflict of interest.

Subjects:

Research Funding:

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:

  • 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

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

Tools:

Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 111, Number 15

Publisher:

, Pages 5706-5711

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

Copyright © 2020 National Academy of Sciences.

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