title: Activation of AMPK-induced autophagy ameliorates Huntington disease pathology in vitro.
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 STHdh 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.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Walter
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany; QPS Austria, 8074 Grambach, Austria.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Clemens
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Amelie J
authors.initials: AJ
authors.lastname: Müller
authors.affiliation: Division of General Pathology and Pathological Anatomy, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Fallier-Becker
authors.affiliation: Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Tassula
authors.initials: T
authors.lastname: Proikas-Cezanne
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Metzger
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tuebingen, Germany. Electronic address: hoa.nguyen@med.uni-tuebingen.de.
authors.forename: Huu Phuc
authors.initials: HP
authors.lastname: Nguyen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001713:Biphenyl Compounds; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D055879:Gene Knock-In Techniques / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011753:Pyrones / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001713:Biphenyl Compounds; D011753:Pyrones; D013876:Thiophenes; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMPK; Autophagy; Huntingtin; Huntington disease; mTOR independent