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

Tz Chuen Ju, Hui Mei Chen, Jiun Tsai Lin, Ching Pang Chang, Wei Cheng Chang, Jheng Jie Kang, Cheng Pu Sun, Mi Hua Tao, Pang Hsien Tu, Chen Chang, Dennis W Dickson, Yijuang Chern

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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.

Original languageEnglish (US)
Pages (from-to)209-227
Number of pages19
JournalJournal of Cell Biology
Volume194
Issue number2
DOIs
StatePublished - Jul 25 2011

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Corpus Striatum
Huntington Disease
Adenosine Monophosphate
Protein Kinases
Poisons
Cell Nucleus
Neurodegenerative Diseases
Transgenic Mice
Atrophy
Protein Isoforms
Homeostasis
Cell Death
Down-Regulation
Neurons
Brain

ASJC Scopus subject areas

  • Cell Biology

Cite this

Ju, T. C., Chen, H. M., Lin, J. T., Chang, C. P., Chang, W. C., Kang, J. J., ... Chern, Y. (2011). Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington's disease. Journal of Cell Biology, 194(2), 209-227. https://doi.org/10.1083/jcb.201105010

Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington's disease. / Ju, Tz Chuen; Chen, Hui Mei; Lin, Jiun Tsai; Chang, Ching Pang; Chang, Wei Cheng; Kang, Jheng Jie; Sun, Cheng Pu; Tao, Mi Hua; Tu, Pang Hsien; Chang, Chen; Dickson, Dennis W; Chern, Yijuang.

In: Journal of Cell Biology, Vol. 194, No. 2, 25.07.2011, p. 209-227.

Research output: Contribution to journalArticle

Ju, TC, Chen, HM, Lin, JT, Chang, CP, Chang, WC, Kang, JJ, Sun, CP, Tao, MH, Tu, PH, Chang, C, Dickson, DW & Chern, Y 2011, 'Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington's disease', Journal of Cell Biology, vol. 194, no. 2, pp. 209-227. https://doi.org/10.1083/jcb.201105010
Ju, Tz Chuen ; Chen, Hui Mei ; Lin, Jiun Tsai ; Chang, Ching Pang ; Chang, Wei Cheng ; Kang, Jheng Jie ; Sun, Cheng Pu ; Tao, Mi Hua ; Tu, Pang Hsien ; Chang, Chen ; Dickson, Dennis W ; Chern, Yijuang. / Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington's disease. In: Journal of Cell Biology. 2011 ; Vol. 194, No. 2. pp. 209-227.
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