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Pharmacological Activation of Sirt1 Ameliorates Polyglutamine-Induced Toxicity through the Regulation of Autophagy

Title
Pharmacological Activation of Sirt1 Ameliorates Polyglutamine-Induced Toxicity through the Regulation of Autophagy
Author
안주홍
Keywords
BREAST-CANCER CELLS; BETA-LAPACHONE; HUNTINGTONS-DISEASE; CAENORHABDITIS-ELEGANS; MUTANT HUNTINGTIN; INTRANUCLEAR INCLUSIONS; MOUSE MODELS; APOPTOSIS; AGGREGATION; INDUCTION
Issue Date
2013-06
Publisher
PUBLIC LIBRARY SCIENCE
Citation
PLoS ONE, 10 June 2013, 8(6), pp.e64953
Abstract
Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington's disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, beta-lapachone (beta-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with beta-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a pathogenic polyQ stretch fused to green fluorescent protein (HttEx1(97Q)-GFP). beta-lap increased autophagy in SH-SY5Y cells, as evidenced by the increased formation of LC3-II and autolysosomes. Furthermore, beta-lap reduced HttEx1(97Q)-GFP aggregation, which was significantly prevented by co-incubation with 3-methyladenine, an inhibitor of autophagy. beta-lap increased Sirt1 activity, as shown by the increased deacetylation of the Sirt1 substrates, PARP-1 and Atg5, and the nuclear translocation of FOXO1. Both the induction of autophagy and attenuation of HttEx1(97Q)-GFP aggregation by beta-lap were significantly prevented by co-incubation with sirtinol, a general sirtuin inhibitor or by co-transfection with shRNA against Sirt1. The pro-autophagic actions of beta-lap were further investigated in a transgenic Caenorhabditis elegans (C. elegans) line that expressed Q67 fused to cyanine fluorescent protein (Q67). Notably, beta-lap reduced the number of Q67 puncta and restored Q67-induced defects in motility, which were largely prevented by pre-treatment with RNAi against sir-2.1, the C. elegans orthologue of Sirt1. Collectively, these data suggest that beta-lap induces autophagy through activation of Sirt1, which in turn leads to a reduction in polyQ aggregation and cellular toxicity. Thus, beta-lap provides a novel therapeutic opportunity for the treatment of HD.
URI
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064953http://hdl.handle.net/20.500.11754/45625
ISSN
1932-6203
DOI
10.1371/journal.pone.0064953
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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