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Resources » Paper

Vazquez-manrique, Rafael et al. (2011) International Worm Meeting "AMPK activation is protective in models of neuron dysfunction and death in Huntington's disease."

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  • Comments on Vazquez-manrique, Rafael et al. (2011) International Worm Meeting "AMPK activation is protective in models of neuron dysfunction and death in Huntington's disease." (0)

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    Status:
    Publication type:
    Meeting_abstract
    WormBase ID:
    WBPaper00039000

    Vazquez-manrique, Rafael, Cambon, Karine, Offner, Nicolas, Darbois, Aurelie, Orfila, Anne-marie, Deglon, Nicole, & Neri, Christian (2011). AMPK activation is protective in models of neuron dysfunction and death in Huntington's disease presented in International Worm Meeting. Unpublished information; cite only with author permission.

    Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the huntingtin protein (Htt). Expression of the first exon of Htt containing an expanded polyQ produces neuronal dysfunction and axonal dystrophy in mechanosensory neurons in C. elegans (Parker et al., 2001). Genetic pathway analysis using this nematode model has emphasized a role for the longevity-promoting factor daf-16/FoxO in the protection of neurons from expanded polyQ toxicity (Parker et al., 2005). Here, we investigated the role of AMP-activated protein kinase (AMPK), a well-known energy sensor involved in lifespan and health span extension, on neuronal dysfunction in expanded-polyQ nematodes and vulnerability to cell death in mutant Htt striatal cells (HdhQ111 knock-in mice). In C. elegans, activating this enzyme (aak-2/AMPK) with metformin reduces the neuronal dysfunction caused by expanded polyQ expression. In contrast, aak-2 mutants show enhanced neuronal impairment. In striatal cells from HdhQ111 knock-in mice, reducing AMPK levels by siRNA treatment enhances the susceptibility to cell death of mutant htt cells, and metformin treatment has the opposite effect. Additionally, overexpressing AMPK reduced striatal neurodegeneration in a rat lentiviral-based fragment model of HD pathogenesis. Collectively, our results suggest that AMPK activation has therapeutic potential to protect from neuron dysfunction and degeneration in HD.

    Affiliations:
    - Laboratory of Neuronal Cell Biology and Pathology, INSERM U894, 75014 Paris, France
    - Commissariat a l'Energie Atomique (CEA), Institut d'Imagerie Biomedicale (I2BM), Molecular Imaging Research Center (MIRCen), Orsay, France
    - Centre National de la Recherche Scientifique (CNRS), Unite de Recherche Associee CEA-CNRS 2210, Orsay, France


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