Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity

Hui Zhou, Fengli Cao, Zhishan Wang, Zhao Xue Yu, Huu Phuc Nguyen, Joy Evans, Shi Hua Li, Xiao Jiang Li

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

Although NH2-terminal mutant huntingtin (htt) fragments cause neurological disorders in Huntington's disease (HD), it is unclear how toxic htt fragments are generated and contribute to the disease process. Here, we report that complex NH2-terminal mutant htt fragments smaller than the first 508 amino acids were generated in htt-transfected cells and HD knockin mouse brains. These fragments constituted neuronal nuclear inclusions and appeared before neurological symptoms. The accumulation and aggregation of these htt fragments were associated with an age-dependent decrease in proteasome activity and were promoted by inhibition of proteasome activity. These results suggest that decreased proteasome activity contributes to late onset htt toxicity and that restoring the ability to remove NH 2-terminal fragments will provide a more effective therapy for HD than inhibiting their production.

Original languageEnglish
Pages (from-to)109-118
Number of pages10
JournalJournal of Cell Biology
Volume163
Issue number1
DOIs
StatePublished - Oct 13 2003

Keywords

  • Aggregates
  • Aging
  • Huntington's disease
  • Polyglutamine
  • Proteolysis

ASJC Scopus subject areas

  • Cell Biology

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