Huntingtin Forms Toxic NH2-Terminal Fragment Complexes That Are Promoted by the Age-Dependent Decrease in Proteasome Activity

• Published in: The Journal of cell biology Vol. 163; no. 1; pp. 109 - 118
• Main Authors: Zhou, Hui, Cao, Fengli, Wang, Zhishan, Yu, Zhao-Xue, Nguyen, Huu-Phuc, Evans, Joy, Li, Shi-Hua, Li, Xiao-Jiang
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 13.10.2003; The Rockefeller University Press
• Subjects: Animals; Antibodies; Antibodies - immunology; Brain - metabolism; Cell aggregates; Cell nucleus; Cells; Cultured cells; Cysteine Endopeptidases - metabolism; HEK293 cells; Humans; Huntingtin Protein; Huntington disease; Huntington Disease - metabolism; Mice; Multienzyme Complexes - metabolism; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; Nerve Tissue Proteins - metabolism; Neurons; Nuclear Proteins - genetics; Nuclear Proteins - immunology; Nuclear Proteins - metabolism; Peptides - metabolism; Proteasome Endopeptidase Complex; Proteins
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200306038

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.