Regulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1
Regulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1
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DOI：
10.1074/jbc.m600364200
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发表时间：
2006-05-19
影响因子：
4.8
通讯作者：
Yuan, Junying
中科院分区：
文献类型：
--
作者：
Shibata, Mamoru;Lu, Tao;Yuan, Junying
突变型亨廷顿蛋白与扩展的聚谷氨酰胺在细胞内的积累提供了对于亨廷顿病的发病机制至关重要的背景依赖性细胞毒性（Everett, C. M. 和 Wood, N. W. (2004) Brain 127, 2385-2405）。在这里，我们证明突变亨廷顿蛋白的积累对自噬必需基因 beclin 1 的表达高度敏感。此外，我们发现积累的突变亨廷顿蛋白会招募 Beclin 1 并损害 Beclin 1 介导的长寿命蛋白质周转。因此，亨廷顿病患者脆弱神经元群中 Beclin 1 的隔离可能会进一步降低 Beclin 1 功能和突变亨廷顿蛋白的自噬降解。最后，我们证明了人脑中 beclin 1 的表达以年龄依赖性方式减少。因为 beclin 1 基因是单倍体，不足以调节自噬体功能 (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. 投资。 112、1809-1820； Yue, Z.、Jin, S.、Yang, C.、Levine, A. J. 和 Heintz, N. (2003) Proc。国家。阿卡德。科学。 U.S.A. 100, 15077 15082)，我们提出beclin 1表达的年龄依赖性降低可能导致衰老过程中自噬活性的降低，进而促进突变型Htt的积累 以及疾病的进展。
Intracellular 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.