Shibata Mamoru, Lu Tao, Furuya Tsuyoshi, Degterev Alexei, Mizushima Noboru, Yoshimori Tamotsu, MacDonald Marcy, Yankner Bruce, Yuan Junying
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2006 May 19;281(20):14474-85. doi: 10.1074/jbc.M600364200. Epub 2006 Mar 6.
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.
含有扩展多聚谷氨酰胺的突变型亨廷顿蛋白在细胞内的积累会产生一种对亨廷顿病发病机制至关重要的依赖于环境的细胞毒性（埃弗雷特，C.M.，和伍德，N.W.（2004年）《大脑》127卷，2385 - 2405页）。在此我们证明，突变型亨廷顿蛋白的积累对自噬所必需的基因贝克林1的表达高度敏感。此外，我们表明积累的突变型亨廷顿蛋白招募贝克林1并损害贝克林1介导的长寿命蛋白周转。因此，在亨廷顿病患者易损神经元群体中隔离贝克林1可能会进一步降低贝克林1的功能以及突变型亨廷顿蛋白的自噬降解。最后，我们证明在人类大脑中贝克林1的表达以年龄依赖性方式降低。由于贝克林1基因在调节自噬体功能方面单倍体不足（曲，X.，于，J.，巴加特，G.，古谷，N.，希布舒什，H.，特罗克塞尔，A.，罗森，J.，埃斯凯林嫩，E.L.，水岛，N.，大隅，Y.，卡托雷蒂，G.，和莱文，B.（2003年）《临床研究杂志》112卷，1809 - 1820页；岳，Z.，金，S.，杨，C.，莱文，A.J.，和海因茨，N.（2003年）《美国国家科学院院刊》100卷，15077 - 15082页），我们提出贝克林1表达的年龄依赖性降低可能导致衰老过程中自噬活性降低，这反过来促进突变型Htt的积累和疾病进展。
