Caspase 6 has a protective role in SOD1G93A transgenic mice

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In amyotrophic lateral sclerosis (ALS), it has been suggested that the process of neurodegeneration starts at the neuromuscular junction and is propagated back along axons towards motor neurons. Caspase-dependent pathways are well established as a cause of motor neuron death, and recent work in other disease models indicated a role for caspase 6 in axonal degeneration. Therefore we hypothesised that caspase 6 may be involved in motor neuron death in ALS. To investigate the role of caspase 6 in ALS we profiled protein levels of caspase-6 throughout disease progression in the ALS mouse model SOD1G93A; this did not reveal differences in caspase 6 levels during disease. To investigate the role of caspase 6 further we generated a colony with SOD1G93A transgenic mice lacking caspase 6. Analysis of the transgenic SOD1G93A; Casp6−/− revealed an exacerbated phenotype with motor dysfunction occurring earlier and a significantly shortened lifespan when compared to transgenic SOD1G93A; Casp6+/+ mice. Immunofluorescence analysis of the neuromuscular junction revealed no obvious difference between caspase 6+/+ and caspase 6−/− in non-transgenic mice, while the SOD1G93A transgenic mice showed severe degeneration compared to non-transgenic mice in both genotypes. Our data indicate that caspase-6 does not exacerbate ALS pathogenesis, but may have a protective role.