Journal
NEUROCHEMICAL RESEARCH
Volume 41, Issue 3, Pages 544-553Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-015-1665-3
Keywords
ALS; AMPK; Energy; Metabolism; SOD1; TDP-43
Categories
Funding
- Australian National Health and Medical Research Council [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
- Victorian Government's Operational Infrastructure Support Grant
- Australian Postgraduate Award Scholarship
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available