title: Seeking homeostasis: temporal trends in respiration, oxidation, and calcium in SOD1 G93A Amyotrophic Lateral Sclerosis mice.
abstract: Impairments in mitochondria, oxidative regulation, and calcium homeostasis have been well documented in numerous Amyotrophic Lateral Sclerosis (ALS) experimental models, especially in the superoxide dismutase 1 glycine 93 to alanine (SOD1 G93A) transgenic mouse. However, the timing of these deficiencies has been debatable. In a systematic review of 45 articles, we examine experimental measurements of cellular respiration, mitochondrial mechanisms, oxidative markers, and calcium regulation. We evaluate the quantitative magnitude and statistical temporal trend of these aggregated assessments in high transgene copy SOD1 G93A mice compared to wild type mice. Analysis of overall trends reveals cellular respiration, intracellular adenosine triphosphate, and corresponding mitochondrial elements (Cox, cytochrome c, complex I, enzyme activity) are depressed for the entire lifespan of the SOD1 G93A mouse. Oxidant markers (H2O2, 8OH2'dG, MDA) are initially similar to wild type but are double that of wild type by the time of symptom onset despite early post-natal elevation of protective heat shock proteins. All aspects of calcium regulation show early disturbances, although a notable and likely compensatory convergence to near wild type levels appears to occur between 40 and 80 days (pre-onset), followed by a post-onset elevation in intracellular calcium. The identified temporal trends and compensatory fluctuations provide evidence that the "cause" of ALS may lay within failed homeostatic regulation, itself, rather than any one particular perturbing event or cellular mechanism. We discuss the vulnerabilities of motoneurons to regulatory instability and possible hypotheses regarding failed regulation and its potential treatment in ALS.
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology - Emory University, Atlanta, GA USA.
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Irvin
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology - Emory University, Atlanta, GA USA.
authors.forename: Renaid B
authors.initials: RB
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology - Emory University, Atlanta, GA USA.
authors.forename: Cassie S
authors.initials: CS
authors.lastname: Mitchell
keywords: ALS; Ca2+; energy metabolism; mitochondria; motor neuron disease; oxidative stress