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dc.contributor.authorShibata, Mamoru
dc.contributor.authorLu, Tao
dc.contributor.authorFuruya, Tsuyoshi
dc.contributor.authorDegterev, Alexei
dc.contributor.authorMizushima, Noboru
dc.contributor.authorYoshimori, Tamotsu
dc.contributor.authorMacDonald, Marcy
dc.contributor.authorYankner, Bruce
dc.contributor.authorYuan, Junying
dc.date.accessioned2019-10-05T16:06:17Z
dc.date.issued2006
dc.identifier.citationShibata, Mamoru, Tao Lu, Tsuyoshi Furuya, Alexei Degterev, Noboru Mizushima, Tamotsu Yoshimori, Marcy MacDonald, Bruce Yankner, and Junying Yuan. 2006. “Regulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1.” Journal of Biological Chemistry 281 (20): 14474–85. https://doi.org/10.1074/jbc.m600364200.
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41483567*
dc.description.abstractIntracellular accumulation of mutant Huntingtin with expanded polyglutamine provides a context-dependent cytotoxicity critical for the pathogenesis of Huntington disease (Everett, C. M., and Wood, N. W. (2004) Brain 127, 2385-2405). Here we demonstrate that the accumulation of mutant Huntingtin is highly sensitive to the expression of beclin 1, a gene essential for autophagy. Moreover, we show that the accumulated mutant Huntingtin recruits Beclin 1 and impairs the Beclin 1-mediated long lived protein turnover. Thus, sequestration of Beclin 1 in the vulnerable neuronal population of Huntington disease patients might further reduce Beclin 1 function and autophagic degradation of mutant Huntingtin. Finally, we demonstrate that the expression of beclin 1 decreases in an age-dependent fashion in human brains. Because beclin 1 gene is haploid insufficient in regulating autophagosome function (Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E. L., Mizushima, N., Ohsumi, Y., Cattoretti, G., and Levine, B. (2003) J. Clin. Invest. 112, 1809-1820; Yue, Z., Jin, S., Yang, C., Levine, A. J., and Heintz, N. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 15077 15082), we propose that the age-dependent decrease of beclin 1 expression may lead to a reduction of autophagic activity during aging, which in turn promotes the accumulation of mutant Htt and the progression of the disease.
dc.language.isoen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology
dash.licenseLAA
dc.titleRegulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalThe Journal of Biological Chemistry
dash.depositing.authorYuan, Junying::c7e832b918fc7c2356d6c49fe1a0b135::600
dc.date.available2019-10-05T16:06:17Z
dash.workflow.comments1Science Serial ID 106414
dc.identifier.doi10.1074/jbc.M600364200
dash.source.volume281;20
dash.source.page14474-14485


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