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.

Spinal Cord Metabolic Signatures in Models of Fast- and Slow-Progressing SOD1G93A Amyotrophic Lateral Sclerosis

“…We previously reported a marked decrease of mitochondrial transcripts and ATP production in the ventral portion of the lumbar spinal cord of 129S-G93A mice compared with C57-G93A at onset (Nardo et al, 2013). The unfavorable mitochondrial metabolic state observed in 129S-G93A mice compared with C57-G93A supports the idea that failing homeostatic regulation of these mechanisms may play a role in accelerating the disease (Irvin et al, 2015).…”

Associations of Patient Mood, Modulators of Quality of Life, and Pharmaceuticals with Amyotrophic Lateral Sclerosis Survival Duration

“…Ironically, ALS patients have less overall overt liver disease, and some liver medications have shown positive impacts in ALS [37]. Moreover, the liver is critical for processing drugs and supplements, and plays a critical role in overall homeostasis [67], which is also known to be greatly impacted by ALS, as well as biological aging.…”

A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry

“…There is also a need for the motor‐neuron to adapt protein transcription and translation with related energy demands within a limited time‐frame (Irvin et al . ), a critical process which may condition motor cell survival in neurodegeneration.…”