title: Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease.
abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the α1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.
authors.affiliation: Institute of Neuroscience and 2 Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang Ming University, Taipei 112, Taiwan.
authors.forename: Tz-Chuen
authors.initials: TC
authors.lastname: Ju
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Jiun-Tsai
authors.initials: JT
authors.lastname: Lin
authors.forename: Ching-Pang
authors.initials: CP
authors.lastname: Chang
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Chang
authors.forename: Jheng-Jie
authors.initials: JJ
authors.lastname: Kang
authors.forename: Cheng-Pu
authors.initials: CP
authors.lastname: Sun
authors.forename: Mi-Hua
authors.initials: MH
authors.lastname: Tao
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.forename: Chen
authors.initials: C
authors.lastname: Chang
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology*; D009410:Nerve Degeneration / Q000201:enzymology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C548179:Prkaa1 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human