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Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration


Introduction and aims: The etiology of ALS remains unknown despite the identification of mutated genes in familial and/or sporadic ALS. It is thought that aggregates of disease-causing mutant proteins and RNAs disrupt the normal cellular functions that leads to dying back neuropathy and motor neuron degeneration. Mitochondrial dysfunction is thought to play a major role in the pathology of ALS (1–3). Therefore, restoration of mitochondrial function is likely to cause beneficial effects for the survival of ALS model mice (4).

The objective of this project is to evaluate the effects of oxaloacetate for the neuromuscular function and lifespan of the superoxide dismutase 1 (SOD1) G93A transgenic mice. Oxaloacetate has beneficial effects on mitochondria biogenesis. Systemic administration of oxaloacetate to wild-type mice increased brain expression level of peroxisome proliferator-activated receptor g coactivator 1a (PGC1a), which is a transcriptional co-activator and a master-coordinator of mitochondrial biogenesis (5). Furthermore, oxaloacetate altered levels, distributions or post-translational modifications of proteins and mRNAs in ways that promote mitochondrial biogenesis (PGC1 related co-activator, NRF1, etc.) (5). Oxaloacetate can access the central nervous system by systemic administration in mice (5,6), is neuroprotective in neurodegenerative model mice induced by kainic acid administration (6,7), and prolongs survival of wild-type C. elegans by mimicking caloric restriction (8). However, oxaloacetate has not been tested alone in transgenic rodent models of ALS.

Methods: The oxaloacetate effect was compared in three groups: oxaloacetate treatment from the pre-symptomatic stage, oxaloacetate treatment from the symptomatic stage, and the control group without oxaloacetate. Oxaloacetate was administered systemically to SOD1G93A mice by daily intraperitoneal injection. To evaluate the neuromuscular function, behavior tests were performed prior to oxaloacetate treatment and every 10 days during the treatment until the end stage of the lifespan.

Results and discussion: The pre-symptomatic stage treatment significantly improved the neuromuscular strength. The symptomatic stage treatment significantly delayed the limb paralysis and showed a trend of lifespan expansion. Oxaloacetate treatment from the pre-symptomatic stage group was also analyzed for mitochondrial activity levels using an Oroboros high resolution respirometer and for expression levels of mitochondria biogenesis related proteins. These data suggest that oxaloacetate treatment has a beneficial effect to maintain the neuromuscular function in ALS model mice. This work was supported by grants from KCALSI (HN) and NIH R01NS078214 (HN).

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2. De Vos KJ, et al. Hum Mol Genet. 2007;16:2720.
3. Li Q, et al. Proc Natl Acad Sci Usa. 2010;107:21146.
4. Court FA, et al. Trends in neurosciences 2012.
5. Wilkins HM, et al. Hum Mol Genet. 2014;23:6528.
6. Yamamoto HA, et al. Toxicol Lett. 2003;143:115.
7. Ruban A, et al. Neurodegener Dis. 2015;15:233.
8. Williams DS, et al. Aging Cell. 2009;8:765.



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mitochondria, neuromuscular strength, SOD1G93A mice