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AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is caused by selective loss of upper and lower motor neurons by complex mechanisms that are incompletely understood. Motor neurons are large, highly polarised and excitable cells with unusually high energetic demands to maintain resting membrane potential and propagate action potentials. This leads to higher ATP consumption and mitochondrial metabolism in motor neurons relative to other cells. Here, we review increasing evidence that defective energy metabolism and homeostasis contributes to selective vulnerability and degeneration of motor neurons in ALS. Firstly, we provide a brief overview of major energetic pathways in the CNS, including glycolysis, oxidative phosphorylation and the AMP-activated protein kinase (AMPK) signalling pathway, while highlighting critical metabolic interactions between neurons and astrocytes. Next, we review evidence from ALS patients and transgenic mutant SOD1 mice for weight loss, hypermetabolism, hyperlipidemia and mitochondrial dysfunction in disease onset and progression. Genetic and therapeutic modifiers of energy metabolism in mutant SOD1 mice will also be summarised. We also present evidence that additional ALS-linked proteins, TDP-43 and FUS, lead to energy disruption and mitochondrial defects in motor neurons. Lastly, we review emerging evidence including our own that dysregulation of the AMPK signalling cascade in motor neurons is an early and common event in ALS pathogenesis. We suggest that an imbalance in energy metabolism should be considered an important factor in both progression and potential treatment of ALS.

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Acknowledgments

This work was supported by the Australian National Health and Medical Research Council (Project Grant 1008910), Stafford Fox Medical Research Foundation, MND Research Institute of Australia (Ted Dimmick Memorial MND Research Grant), Bethlehem Griffiths Research Foundation, Cavalier Courage MND Research Grant and the Victorian Government’s Operational Infrastructure Support Grant. N.P. is supported by an Australian Postgraduate Award Scholarship.

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  1. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Nirma D. Perera & Bradley J. Turner

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Special issue: In honor of Prof. Philip Beart.

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Perera, N.D., Turner, B.J. AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis. Neurochem Res 41, 544–553 (2016). https://doi.org/10.1007/s11064-015-1665-3

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