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 NH2-terminal fragments will provide a more effective therapy for HD than inhibiting their production.
Skip Nav Destination
Article navigation
13 October 2003
Article|
October 13 2003
Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity
Hui Zhou,
Hui Zhou
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Fengli Cao,
Fengli Cao
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Zhishan Wang,
Zhishan Wang
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Zhao-Xue Yu,
Zhao-Xue Yu
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Huu-Phuc Nguyen,
Huu-Phuc Nguyen
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Joy Evans,
Joy Evans
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Shi-Hua Li,
Shi-Hua Li
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Xiao-Jiang Li
Xiao-Jiang Li
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Search for other works by this author on:
Hui Zhou
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Fengli Cao
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Zhishan Wang
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Zhao-Xue Yu
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Huu-Phuc Nguyen
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Joy Evans
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Shi-Hua Li
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
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: [email protected]
Abbreviations used in this paper: 3-NP, 3-nitropropionic acid; ALLN, N-acetyl-leucinal-leucinal-norleucinal; ANOVA, analysis of variance; HD, Huntington's disease; htt, huntingtin; HEK293, human embryonic kidney 293; polyQ, polyglutamine.
Received:
June 06 2003
Accepted:
August 28 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 163 (1): 109–118.
Article history
Received:
June 06 2003
Accepted:
August 28 2003
Citation
Hui Zhou, Fengli Cao, Zhishan Wang, Zhao-Xue Yu, Huu-Phuc Nguyen, Joy Evans, Shi-Hua Li, Xiao-Jiang Li; Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity . J Cell Biol 13 October 2003; 163 (1): 109–118. doi: https://doi.org/10.1083/jcb.200306038
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Sign in via your Institution
Sign in via your InstitutionEmail alerts
Advertisement
Advertisement