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J. Cell Biol. 194 (2): 209-227

Copyright © 2011 by the Rockefeller University Press.

Article

Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s disease

Tz-Chuen Ju1,3, Hui-Mei Chen3, Jiun-Tsai Lin3, Ching-Pang Chang3, Wei-Cheng Chang1, Jheng-Jie Kang1, Cheng-Pu Sun2, Mi-Hua Tao3, Pang-Hsien Tu3, Chen Chang3, Dennis W. Dickson4, , and Yijuang Chern1,3

1 Institute of Neuroscience and 2 Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang Ming University, Taipei 112, Taiwan
3 Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
4 Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224

Correspondence to Yijuang Chern: bmychern{at}ibms.sinica.edu.tw

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.

Abbreviations: AAV, adeno-associated virus • AD, Alzheimer’s disease • AICAR, aminoimidazole carboxamide riboside • AMPK, AMP-activated protein kinase • CC, compound C • CREB, cAMP response element binding • CSC, 8-[-3-chlorostyryl]-caffeine • GAPDH, glyceraldehyde-3-phosphate dehydrogenase • HD, Huntington’s disease • hrGFP, humanized Renilla GFP • Htt, Huntingtin • mHtt, mutant Htt • MRI, magnetic resonance imaging • NES, nuclear export signal • NeuN, neuronal nuclei • PARP, poly (ADP-ribose) polymerase • PB, phosphate buffer • polyQ, polyglutamine • qPCR, quantitative PCR • RIPA, radioimmunoprecipitation assay • VBR, ventricle to brain ratio • WT, wild type

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