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Article Dans Une Revue Human Molecular Genetics Année : 2016

AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington's disease

Rafael P. Vazquez-Manrique
  • Fonction : Auteur
Francesca Farina
Karine Cambon
Maria Dolores Sequedo
  • Fonction : Auteur
Alex J. Parker
  • Fonction : Auteur
Jose Maria Millan
  • Fonction : Auteur
Andreas Weiss
  • Fonction : Auteur
Nicole Deglon
  • Fonction : Auteur
Christian Neri

Résumé

The adenosine monophosphate activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. However, in Huntington's disease (HD), AMPK may be activated in the striatum of HD mice at a late, post-symptomatic phase of the disease, and high-dose regiments of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide may worsen neuropathological and behavioural phenotypes. Here, we revisited the role of AMPK in HD using models that recapitulate the early features of the disease, including Caenorhabditis elegans neuron dysfunction before cell death and mouse striatal cell vulnerability. Genetic and pharmacological manipulation of aak-2/AMPKa shows that AMPK activation protects C. elegans neurons from the dysfunction induced byhumanexon-1 huntingtin (Htt) expression, in a daf-16/forkhead box O-dependent manner. Similarly, AMPK activation using genetic manipulation and low-dose metformin treatment protects mouse striatal cells expressing full-length mutant Htt (mHtt), counteracting their vulnerability to stress, with reduction of soluble mHtt levels by metformin and compensation of cytotoxicity by AMPK alpha 1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-gamma 1 to mouse striata slows down the neurodegenerative effects of mHtt. Collectively, these data highlight the importance of considering the dynamic of HD for assessing the therapeutic potential of stress-response targets in the disease. We postulate that AMPK activation is a compensatory response and valid approach for protecting dysfunctional and vulnerable neurons in HD.

Dates et versions

hal-01545502 , version 1 (22-06-2017)

Identifiants

Citer

Rafael P. Vazquez-Manrique, Francesca Farina, Karine Cambon, Maria Dolores Sequedo, Alex J. Parker, et al.. AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington's disease. Human Molecular Genetics, 2016, 25 (6), pp.1043-1058. ⟨10.1093/hmg/ddv513⟩. ⟨hal-01545502⟩
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