Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity.
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.
Zhou
Hui
H
Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322, USA.
Cao
Fengli
F
Wang
Zhishan
Z
Yu
Zhao-Xue
ZX
Nguyen
Huu-Phuc
HP
Evans
Joy
J
Li
Shi-Hua
SH
Li
Xiao-Jiang
XJ
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001921:Brain / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex
D000906:Antibodies; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex