title: AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington's disease.
abstract: 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/AMPKα shows that AMPK activation protects C. elegans neurons from the dysfunction induced by human exon-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 AMPKα1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-γ1 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.
authors.affiliation: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France, Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France, Molecular, Cellular and Genomic Biomedicine Research Group, Health Research Institute-La Fe and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain, christian.neri@inserm.fr rafael_vazquez@iislafe.es.
authors.forename: Rafael P
authors.initials: RP
authors.lastname: Vázquez-Manrique
authors.affiliation: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France, Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Farina
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), MIRCen, Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Cambon
authors.affiliation: Molecular, Cellular and Genomic Biomedicine Research Group, Health Research Institute-La Fe and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Dolores Sequedo
authors.affiliation: CRCHUM, Montréal, Canada, Department de Neurosciences, Faculté de médecine, Université de Montréal, Montréal, Canada.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Parker
authors.affiliation: Molecular, Cellular and Genomic Biomedicine Research Group, Health Research Institute-La Fe and CIBER de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Millán
authors.affiliation: Evotec AG, Manfred Eigen Campus, Hamburg, Germany and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), MIRCen, Department of Clinical Neurosciences (DNC), Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.affiliation: CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology, Paris, France, Sorbonnes Universités, University Pierre and Marie Curie (UPMC) Univ Paris 06, Paris, France, christian.neri@inserm.fr rafael_vazquez@iislafe.es.
authors.forename: Christian
authors.initials: C
authors.lastname: Neri
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D017173:Caenorhabditis elegans; D016923:Cell Death / Q000502:physiology; D003342:Corpus Striatum / Q000201:enzymology; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D017072:Neostriatum / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D012263:Ribonucleosides / Q000494:pharmacology
chemical_list: D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; C011651:acadesine; D055372:AMP-Activated Protein Kinases