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Published 27 February 2006. doi:10.1083/jcb.200510065
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 5, 719-731
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Article

 Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway

Ai Yamamoto, M. Laura Cremona, and James E. Rothman

The Judith P. Sulzberger Columbia Genome Center, Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032

Correspondence to James E. Rothman: jr2269{at}columbia.edu

Conditional mouse models of polyglutamine diseases, such as Huntington's disease (HD), have revealed that cells can clear accumulated pathogenic proteins if the continuous production of the mutant transgene is halted. Invariably, the clearance of the protein leads to regression of the disease symptoms in mice. In light of these findings, it is critical to determine the pathway responsible for alleviating this protein accumulation to define targets to fight these diseases. In a functional genetic screen of HD, we found that activation of insulin receptor substrate-2, which mediates the signaling cascades of insulin and insulin-like growth factor 1, leads to a macroautophagy-mediated clearance of the accumulated proteins. The macroautophagy is triggered despite activation of Akt, mammalian target of rapamycin (mTOR), and S6 kinase, but still requires proteins previously implicated in macroautophagy, such as Beclin1 and hVps34. These findings indicate that the accumulation of mutant protein can lead to mTOR-independent macroautophagy and that lysosome-mediated degradation of accumulated protein differs from degradation under conditions of starvation.

Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; ANOVA, analysis of variance; dox, doxycycline; HD, Huntington's disease; htt, huntingtin protein mutant; IGF-1, insulin-like growth factor 1; IL, interleukin; INCA, InCell Analyzer; IRS, insulin receptor substrate; LAMP, lysosome-associated membrane protein; MA, methyladenine; mCFP, monomeric enhanced CFP (L221K mutation); mTOR, mammalian target of rapamycin; N2a, Neuro2a cell lines; P70S6K, p70 s6 kinase; PI3P, PtdIns[3]phosphate; polyQ, polyglutamine; PtdIns3K, phosphatidylinositol 3-kinase; siIRS, small interfering IRS; siRNA, small interfering RNA.


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