Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease
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 mut...
| Main Authors: | , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Society for Neuroscience
2012
|
| Online Access: | http://hdl.handle.net/1721.1/72527 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1826213777806196736 |
|---|---|
| author | Lim, M. A. Selak, M. A. Xiang, Z. Krainc, Dimitri Neve, Rachael L. Kraemer, B. C. Watts, J. L. Kalb, R. G. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Lim, M. A. Selak, M. A. Xiang, Z. Krainc, Dimitri Neve, Rachael L. Kraemer, B. C. Watts, J. L. Kalb, R. G. |
| author_sort | Lim, M. A. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:54:39Z |
| format | Article |
| id | mit-1721.1/72527 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:54:39Z |
| publishDate | 2012 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/725272022-09-29T16:58:37Z Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease Lim, M. A. Selak, M. A. Xiang, Z. Krainc, Dimitri Neve, Rachael L. Kraemer, B. C. Watts, J. L. Kalb, R. G. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. Neve, Rachael L. 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. 2012-09-05T17:48:56Z 2012-09-05T17:48:56Z 2012-01 2011-11 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/72527 Lim, M. A. et al. “Reduced Activity of AMP-Activated Protein Kinase Protects Against Genetic Models of Motor Neuron Disease.” Journal of Neuroscience 32.3 (2012): 1123–1141. https://orcid.org/0000-0002-3854-5968 en_US http://dx.doi.org/10.1523/jneurosci.6554-10.2012 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience SFN |
| spellingShingle | Lim, M. A. Selak, M. A. Xiang, Z. Krainc, Dimitri Neve, Rachael L. Kraemer, B. C. Watts, J. L. Kalb, R. G. Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease |
| title | Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease |
| title_full | Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease |
| title_fullStr | Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease |
| title_full_unstemmed | Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease |
| title_short | Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease |
| title_sort | reduced activity of amp activated protein kinase protects against genetic models of motor neuron disease |
| url | http://hdl.handle.net/1721.1/72527 https://orcid.org/0000-0002-3854-5968 |
| work_keys_str_mv | AT limma reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease AT selakma reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease AT xiangz reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease AT kraincdimitri reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease AT neverachaell reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease AT kraemerbc reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease AT wattsjl reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease AT kalbrg reducedactivityofampactivatedproteinkinaseprotectsagainstgeneticmodelsofmotorneurondisease |