Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1.
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.
Shibata
Mamoru
M
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Lu
Tao
T
Furuya
Tsuyoshi
T
Degterev
Alexei
A
Mizushima
Noboru
N
Yoshimori
Tamotsu
T
MacDonald
Marcy
M
Yankner
Bruce
B
Yuan
Junying
J
D000328:Adult; D000369:Aged, 80 and over; D000375:Aging; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism*; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins