The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1
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Wu, Jun-chao
Lin, Fang
Qi, Lin
Wang, Yan
Yoder, Jennifer
Qin, Zheng-hong
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https://doi.org/10.1038/aps.2012.14Metadata
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Wu, Jun-chao, Lin Qi, Yan Wang, Kimberly B Kegel, Jennifer Yoder, Marian Difiglia, Zheng-hong Qin, and Fang Lin. 2012. “The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1.” Acta Pharmacologica Sinica 33 (6): 743-751. doi:10.1038/aps.2012.14. http://dx.doi.org/10.1038/aps.2012.14.Abstract
Aim: Huntingtin protein (Htt) was a neuropathological hallmark in human Huntington's Disease. The study aimed to investigate whether the macroautophagy regulator, Beclin1, was involved in the degradation of Htt. Methods: PC12 cells and primary cultured brain neurons of rats were examined. pDC316 adenovirus shuttle plasmid was used to mediate the expression of wild-type Htt-18Q-552 or mutant Htt-100Q-552 in PC12 cells. The expression of the autophagy-related proteins LC3 II and Beclin1, as well as the lysosome-associated enzymes Cathepsin B and L was evaluated using Western blotting. The locations of Beclin1 and Htt were observed with immunofluorescence and confocal microscope. Results: Htt552 expression increased the expression of LC3 II, Beclin1, cathepsin B and L in autophagy/lysosomal degradation pathway. Treatment with the autophagy inhibitor 3-MA or the proteasome inhibitors lactacystin and MG-132 increased Htt552 levels in PC12 cells infected with Ad-Htt-18Q-552 or Ad-Htt-100Q-552. The proteasome inhibitor caused a higher accumulation of Htt552-18Q than Htt552-100Q, and the autophagy inhibitor resulted in a higher accumulation of Htt552-100Q than Htt552-18Q. Similar results were observed in primary cultured neurons infected with adenovirus. In Htt552-expressing cells, Beclin1 was redistributed from the nucleus to the cytoplasm. Htt siRNA prevented Beclin1 redistribution in starvation conditions. Blockade of Beclin1 nuclear export by leptomycin B or Beclin1 deficiency caused by RNA interference induced the formation of mHtt552 aggregates. Conclusion: Beclin1 regulates the accumulation of Htt via macroautophagy.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010368/pdf/Terms of Use
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