title: Early ALS-type gait abnormalities in AMP-dependent protein kinase-deficient mice suggest a role for this metabolic sensor in early stages of the disease.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motoneurons. While the principal cause of the disease remains so far unknown, the onset and progression of the pathology are increasingly associated with alterations in the control of cell metabolism. On the basis of the well-known key roles of 5'-adenosine monophosphate-activated protein kinase (AMPK) in sensing and regulating the intracellular energy status, we hypothesized that mice with a genetic deletion of AMPK would develop locomotor abnormalities that bear similarity with those detected in the very early disease stage of mice carrying the ALS-associated mutated gene hSOD1(G93A). Using an automated gait analysis system (CatWalk), we here show that hSOD1(G93A) mice and age-matched mice lacking the neuronal and skeletal muscle predominant α2 catalytic subunit of AMPK showed an altered gait, clearly different from wild type control mice. Double mutant mice lacking AMPK α2 and carrying hSOD1(G93A) showed the same early gait abnormalities as hSOD1(G93A) mice over an age span of 8 to 16 weeks. Taken together, these data support the concept that altered AMPK function and associated bioenergetic abnormalities could constitute an important component in the early pathogenesis of ALS. Therapeutic interventions acting on metabolic pathways could prove beneficial on early locomotor deficits, which are sensitively detectable in rodent models using the CatWalk system.
authors.affiliation: Group of Neuropharmacology, Université catholique de Louvain, B1.54.10, Av. Hippocrate 54, 1200, Brussels, Belgium.
authors.forename: Maxime
authors.initials: M
authors.lastname: Vergouts
authors.affiliation: Alzheimer Dementia Group, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Claudia
authors.initials: C
authors.lastname: Marinangeli
authors.affiliation: Group of Neuropharmacology, Université catholique de Louvain, B1.54.10, Av. Hippocrate 54, 1200, Brussels, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ingelbrecht
authors.affiliation: Group of Neuropharmacology, Université catholique de Louvain, B1.54.10, Av. Hippocrate 54, 1200, Brussels, Belgium.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Genard
authors.affiliation: Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schakman
authors.affiliation: Group of Neuropharmacology, Université catholique de Louvain, B1.54.10, Av. Hippocrate 54, 1200, Brussels, Belgium.
authors.forename: Anthony
authors.initials: A
authors.lastname: Sternotte
authors.affiliation: Group of Neuropharmacology, Université catholique de Louvain, B1.54.10, Av. Hippocrate 54, 1200, Brussels, Belgium.
authors.forename: André-Guilhem
authors.initials: AG
authors.lastname: Calas
authors.affiliation: Group of Neuropharmacology, Université catholique de Louvain, B1.54.10, Av. Hippocrate 54, 1200, Brussels, Belgium. emmanuel.hermans@uclouvain.be.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hermans
mesh_terms: D000263:Adenylate Kinase / Q000172:deficiency* / Q000235:genetics*; D000375:Aging / Q000523:psychology; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000523:psychology*; D000818:Animals; D018450:Disease Progression; D004734:Energy Metabolism / Q000235:genetics; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000378:metabolism* / Q000523:psychology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000263:Adenylate Kinase
keywords: AMP kinase; Amyotrophic lateral sclerosis; CatWalk; Locomotor activity; Metabolism; hSOD1G93A