title: Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease.
abstract: A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease.
authors.affiliation: Department of Pediatrics, Division of Neurology, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Lim
authors.forename: M A
authors.initials: MA
authors.lastname: Selak
authors.forename: Z
authors.initials: Z
authors.lastname: Xiang
authors.forename: D
authors.initials: D
authors.lastname: Krainc
authors.forename: R L
authors.initials: RL
authors.lastname: Neve
authors.forename: B C
authors.initials: BC
authors.lastname: Kraemer
authors.forename: J L
authors.initials: JL
authors.lastname: Watts
authors.forename: R G
authors.initials: RG
authors.lastname: Kalb
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005298:Fertility / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008124:Locomotion / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016472:Motor Neuron Disease / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control*; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology; D009154:Mutation / Q000235:genetics; D010101:Oxygen Consumption / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D021122:Protein Subunits; D015534:Trans-Activators; D014157:Transcription Factors; D000255:Adenosine Triphosphate; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D017346:Protein Serine-Threonine Kinases; C510541:AAK-2 protein, C elegans; D055372:AMP-Activated Protein Kinases