Inhibiting the ubiquitin-proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments (Human Mol Genet, 2010, 19:2445-2455)

報告日期: 2010/12/17
報告時間: 15:10/16:00
報告學生: 李佳玲
講評老師: 莊季瑛

Full Text:

Inhibiting the ubiquitin–proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments

Li X, Wang CE, Huang S, Xu X, Li XJ, Li H, Li S.
Human Molecular Genetics, 2010, 19:2445-2455
Speaker: Chia-Ling Li
Commentator: Dr. Jih-Ing Chuang
Date: 12/17/2010  15:10-16:00
Place: Room 602
Huntington’s disease (HD) is an inherited autosomal-dominant neurodegenerative disease that is caused by expansion of a CAG repeat in the exon 1 of huntingtin gene. The aggregation of mutant huntingtin (htt) proteins affect central nerve system, especially striatum, resulting in motor dysfunctions and cognitive decline. The clearance of misfolded htt by two systems: ubiquitin–proteasome system (UPS) and autophagy. In this study, the authors examined which system is important to remove misfolded htt. The results showed that mutant htt did not alter autophagy activity in HEK293 cells and the brains of HD transgenic/KI mice. Transfected PC12 cells treated with UPS inhibitor showed that mutant htt could cause a neurite outgrowth defect. Furthermore, UPS inhibitor caused greater increase in mutant htt fragments than autophagy inhibitor did. In the HD CAG repeat KI mouse model, inhibition of UPS activity also resulted in preferentially increase the accumulation of toxic N-terminal htt fragments and the formation of htt aggregates in brain. Taken together, clearance of aggregate-prone N-terminal mutant htt fragments is mainly by UPS but not autophagy.
1. Ciechanover, A., Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol, 2005. 6(1): p. 79-87.
2. Rubinsztein, D.C., The roles of intracellular protein-degradation pathways in neurodegeneration. Nature, 2006. 443(7113): p. 780-6.
3. Sarkar, S. and D.C. Rubinsztein, Huntington's disease: degradation of mutant huntingtin by autophagy. FEBS J, 2008. 275(17): p. 4263-70.