Journal article
Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease
The Journal of neuroscience, Vol.32(3), pp.1123-1141
01/18/2012
Handle:
https://hdl.handle.net/2376/113271
PMCID: PMC3742882
PMID: 22262909
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.
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Details
- Title
- Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease
- Creators
- M. A Lim - Department of Pediatrics, Division of Neurology, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104M. A Selak - Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814Z Xiang - MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts 02129D Krainc - MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts 02129R. L Neve - Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139B. C Kraemer - Geriatrics Research Foundation and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108, andJ. L Watts - School of Molecular Biosciences, Washington State University, Pullman, Washington 99164R. G Kalb - Department of Pediatrics, Division of Neurology, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104
- Publication Details
- The Journal of neuroscience, Vol.32(3), pp.1123-1141
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- Society for Neuroscience
- Identifiers
- 99900548593901842
- Language
- English
- Resource Type
- Journal article