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

doi:10.1083/jcb.200306038

Published 13 October 2003. doi:10.1083/jcb.200306038

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© The Rockefeller University Press, 0021-9525/2003/10/109 $8.00
The Journal of Cell Biology, Volume 163, Number 1, 109-118

Article

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 and Xiao-Jiang Li

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322

Address correspondence to Xiao-Jiang Li, Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322. Tel.: (404) 727-3290. Fax: (404) 727-3949. email: xiaoli{at}genetics.emory.edu

Although NH₂-terminal mutant huntingtin (htt) fragments causeneurological disorders in Huntington's disease (HD), it is unclearhow toxic htt fragments are generated and contribute to thedisease process. Here, we report that complex NH₂-terminal mutanthtt fragments smaller than the first 508 amino acids were generatedin htt-transfected cells and HD knockin mouse brains. Thesefragments constituted neuronal nuclear inclusions and appearedbefore neurological symptoms. The accumulation and aggregationof these htt fragments were associated with an age-dependentdecrease in proteasome activity and were promoted by inhibitionof proteasome activity. These results suggest that decreasedproteasome activity contributes to late onset htt toxicity andthat restoring the ability to remove NH₂-terminal fragmentswill provide a more effective therapy for HD than inhibitingtheir production.

Key Words: Huntington's disease; polyglutamine; proteolysis; aging; aggregates

Abbreviations used in this paper: 3-NP, 3-nitropropionic acid;ALLN, N-acetyl-leucinal-leucinal-norleucinal; ANOVA, analysisof variance; HD, Huntington's disease; htt, huntingtin; HEK293,human embryonic kidney 293; polyQ, polyglutamine.

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