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Activation of AMPK-induced autophagy ameliorates Huntington disease pathology in vitro.

Authors :
Walter, Carolin
Clemens, Laura E.
Müller, Amelie J.
Fallier-Becker, Petra
Proikas-Cezanne, Tassula
Riess, Olaf
Metzger, Silke
Nguyen, Huu Phuc
Source :
Neuropharmacology. Sep2016, Vol. 108, p24-38. 15p.
Publication Year :
2016

Abstract

The expansion of a polyglutamine repeat in huntingtin (HTT) causes Huntington disease (HD). Although the exact pathogenesis is not entirely understood, mutant huntingtin (mHTT) causes disruption of various cellular functions, formation of aggregates and ultimately cell death. The process of autophagy is the main degradation pathway for mHTT, and various studies have demonstrated that the induction of autophagy leads to an amelioration of aggregate formation and an increase in cell viability. Commonly, this is achieved by inhibition of the mammalian target of rapamycin (mTOR), a prominent regulator of cell metabolism. Alternatively, non-canonical AMPK or mTOR-independent autophagy regulation has been recognized. Given mTOR's involvement in major cellular pathways besides autophagy, its inhibition may come with potentially detrimental effects. Here, we investigated if AMPK activation may provide a target for the induction of autophagy in an mTOR-independent manner. We demonstrate that activation of AMPK by A769662 and overexpression of a constitutively active form of AMPKα in ST Hdh cells and mouse embryonic fibroblasts (MEFs), leads to increased expression of the autophagosomal markers LC3 and p62, suggesting efficient autophagy induction. The induction of autophagy was independent of mTOR, and accompanied by a decrease of mHTT-containing aggregates as well as improved cell viability. Therefore, we validated AMPK as a promising therapeutic target to treat HD, and identified A769662 as a potential therapeutic compound to facilitate the clearance of mHTT. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00283908
Volume :
108
Database :
Academic Search Index
Journal :
Neuropharmacology
Publication Type :
Academic Journal
Accession number :
116158511
Full Text :
https://doi.org/10.1016/j.neuropharm.2016.04.041