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Sci. Signal., 2 August 2011
Vol. 4, Issue 184, p. ec215
[DOI: 10.1126/scisignal.4184ec215]

EDITORS' CHOICE

Neurodegeneration A Nuclear Movement for Neuronal Death

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Huntington’s disease (HD), a neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene, is associated with various metabolic abnormalities. Noting that a mouse model of HD shows aberrant activation of adenosine monophosphate–activated protein kinase (AMPK, a protein that mediates metabolic responses to changes in cellular energy status) in the striatum (a brain region affected in HD), Ju et al. explored its role in HD. Immunofluorescence analysis of striatal neurons from individuals with HD, and from HD mice, showed nuclear accumulation of the activated form of AMPK, which is phosphorylated on Thr172, whereas activated AMPK in neurons from people and mice without HD was mainly cytoplasmic. Analyses of mouse striata and striatal cell lines revealed that mutant huntingtin (mHtt) specifically promoted the activation and nuclear enrichment of the AMPK α1 isoform (AMPK-α1). Chronic treatment with AICAR (aminoimidazole carboxamide riboside), which increased striatal AMPK activation and AMPK-α1 nuclear localization, enhanced neurodegeneration in HD mice. Analyses of AMPK-α1 mutants targeted to the nucleus or cytoplasm indicated that the nuclear localization of AMPK-α1 was crucial to its promotion of neuronal degeneration, and pharmacological analysis implicated Ca2+/calmodulin-dependent protein kinase II signaling in the mHtt-mediated activation and nuclear accumulation of AMPK-α1. Striatal neurons of HD mice showed decreased abundance of the antiapoptotic protein Bcl2 and of its transcript, as did a striatal cell line with mHtt, and a combination of pharmacological and mutational analysis implicated this decrease in Bcl2 in neuronal death mediated by active nuclear AMPK-α1. Indeed, Bcl2 overexpression enhanced the survival of striatal neurons with mHtt and prevented their death in response to AICAR or nuclear targeting of active AMPK-α1. CGS, an adenosine A2A receptor agonist beneficial to HD mice, inhibited AMPK activation and the nuclear localization of AMPK-α1 through a protein kinase A–dependent pathway and was neuroprotective, rescuing the decrease in Bcl2 transcript in striatal neurons with mHtt. The authors conclude that the aberrant activation and nuclear translocation of AMPK-α1 in striatal neurons provides a previously unappreciated mechanism of mHtt neurotoxicity.

T.-C. Ju, H.-M. Chen, J.-T. Lin, C.-P. Chang, W.-C. Chang, J.-J. Kang, C.-P. Sun, M.-H. Tao, P.-H. Tu, C. Chang, D. W. Dickson, Y. Chern, Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s disease. J. Cell Biol. 194, 209–227 (2011). [Abstract] [Full Text]

Citation: E. M. Adler, A Nuclear Movement for Neuronal Death. Sci. Signal. 4, ec215 (2011).



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