Abstract
Amyotrophic lateral sclerosis (ALS) remains a devastating motor neuron disease with limited treatment options. Oxaloacetate treatment has a neuroprotective effect in rodent models of seizure and neurodegeneration. Therefore, we treated the ALS model superoxide dismutase 1 (SOD1) G93A mice with oxaloacetate and evaluated their neuromuscular function and lifespan. Treatment with oxaloacetate beginning in the presymptomatic stage significantly improved neuromuscular strength measured during the symptomatic stage in the injected mice compared to the non-treated group. Oxaloacetate treatment starting in the symptomatic stage significantly delayed limb paralysis compared with the non-treated group. For lifespan analysis, oxaloacetate treatment did not show a statistically significant positive effect, but the treatment did not shorten the lifespan. Mechanistically, SOD1G93A mice showed increased levels of tumor necrosis factor-α (TNFα) and peroxisome proliferative activated receptor gamma coactivator 1α (PGC-1α) mRNAs in the spinal cord. However, oxaloacetate treatment reverted these abnormal levels to that of wild-type mice. Similarly, the altered expression level of total NF-κB protein returned to that of wild-type mice with oxaloacetate treatment. These results suggest that the beneficial effects of oxaloacetate treatment in SOD1G93A mice may reflect the effects on neuroinflammation or bioenergetic stress.
Highlights
Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor function weakness from upper and lower motor neuron degeneration[1,2,3]
Based on this phenotypic timeline, the effect of oxaloacetate in SOD1G93A mice was compared in three groups with 12 mice per group: a group treated from the presymptomatic stage at 60 days of age, a group treated from the symptomatic stage at 110 days of age[2], and a control group without treatment
These results suggest that oxaloacetate treatment improves neuromuscular function during the symptomatic stages and significantly delays functional decline
Summary
Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor function weakness from upper and lower motor neuron degeneration[1,2,3]. The ALS mouse model S OD1G93A transgenic mice have altered mitochondrial morphology and mitochondrial SOD1 accumulation[5,6]. Oxaloacetate altered the levels, distributions, or post-translational modifications of mRNA and proteins in ways that promote mitochondrial biogenesis This oxaloacetate effect has been observed through effects on PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding protein, p38 MAPK, and AMP-activated protein k inase[23]. Oxaloacetate can penetrate the blood–brain barrier and access the central nervous system following systemic administration[23,24] It shows neuroprotective effects in a neurodegenerative mouse model generated by kainic acid injection[24] and prolongs C. elegans survival by mimicking caloric r estriction[25]. We analyzed gene expression levels in spinal cords and mitochondrial respiratory function to reveal the mechanisms that could mediate the effects of oxaloacetate treatment on S OD1G93A mice
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