Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease and most of the patients die within 3-5 years after disease symptoms are seen. About 90% of the cases the cause of the disease is unknown (sporadic-ALS or S-ALS). About 20% of the cases of the patients that have a family history (F-ALS) have mutations in super oxide dismutase 1 gene (SOD1). Mutant genes from human-ALS patients have been used to construct transgenic mice that overexpress mutant human- SOD1 proteins. These mice develop clinical symptoms very similar to ALS patients such as loss of motor neurons, skeletal muscle atrophy associated with hind limb paralysis and ultimate death. Although, these mouse models have been around for more than a decade the cure is not available for ALS. Recent evidence suggests that neuronal protease calpain is abnormally activated and it may be responsible for degeneration of motor neurons in ALS. The best way to inactivate this protease is to inhibit with its own endogenous inhibitor calpastatin (CAST). We have developed a transgenic mouse line that expresses very high levels of CAST in motor neurons. We will breed CAST Tg mice with mouse model of ALS, hSOD1G93A mice to prevent motor neuron degeneration in ALS mice. Our preliminary data suggests that CAST overexpression in hSOD1G93A mice results in increased survival of motor axons and the double transgenic mice (hSOD1G93A/CAST) live 3.4 months longer than hSOD1G93A mice alone. Based on these observations, we propose that overexpression of CAST in mutant SOD1G93A mice will inhibit motor neuron degeneration and prolong the life span of the animals. The results obtained from our project will help to develop specific calpain inhibitor therapy for ALS. We will use mouse breeding techniques, Southern Blotting, polymerase chain reactions, immunoblotting, immunocytochemistry, electron microscopy and Rotarod tests to achieve our goals.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease and patients die within 3-5 years after disease onset. We will test a protease inhibitor (Calpain-inhibitor, CAST) treatment in mouse model of ALS to prevent motor neuron disease. If we succeed with our approach, we would like to develop specific calpain inhibitor therapy for ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gubitz, Amelie
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Nathan Kline Institute for Psychiatric Research
United States
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Rao, Mala V; Campbell, Jabbar; Palaniappan, Arti et al. (2016) Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice. J Neurochem 137:253-65