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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<jats:italic>in vitro<\/jats:italic>. To investigate the role of AMPK<jats:italic>in vivo<\/jats:italic>, we used<jats:italic>Caenorhabditis elegans<\/jats:italic>models of motor neuron disease.<jats:italic>C. elegans<\/jats:italic>engineered to express human mSOD1 (<jats:italic>G85R<\/jats:italic>) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of<jats:italic>aak-2<\/jats:italic>, the ortholog of the AMPK \u03b12 catalytic subunit in nematodes, improved locomotor behavior and fecundity in<jats:italic>G85R<\/jats:italic>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.<\/jats:p>","DOI":"10.1523\/jneurosci.6554-10.2012","type":"journal-article","created":{"date-parts":[[2012,1,18]],"date-time":"2012-01-18T19:02:25Z","timestamp":1326913345000},"page":"1123-1141","source":"Crossref","is-referenced-by-count":97,"title":["Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease"],"prefix":"10.1523","volume":"32","author":[{"given":"M. A.","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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