Role of calpain-1 in the early phase of experimental ALS

Elevation in [Ca2+]i and activation of calpain-1 occur in central nervous system of SOD1G93A transgenic mice model of amyotrophic lateral sclerosis (ALS), but few data are available about the early stage of ALS. We here investigated the level of activation of the Ca2+-dependent protease calpain-1 in spinal cord of SOD1G93A mice to ascertain a possible role of the protease in the aetiology of ALS. Comparing the events occurring in the 120day old mice, we found that [Ca2+]i and activation of calpain-1 were also increased in the spinal cord of 30day old mice, as indicated by the digestion of some substrates of the protease such as nNOS, αII-spectrin, and the NR2B subunit of NMDA-R. However, the digestion pattern of these proteins suggests that calpain-1 may play different roles depending on the phase of ALS. In fact, in spinal cord of 30day old mice, activation of calpain-1 produces high amounts of nNOS active species, while in 120day old mice enhanced-prolonged activation of calpain-1 inactivates nNOS and down-regulates NR2B. Our data reveal a critical role of calpain-1 in the early phase and during progression of ALS, suggesting new therapeutic approaches to counteract its onset and fatal course.