Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by loss of the survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration of spinal cord motoneurons (MNs), progressive skeletal muscle atrophy, and weakness. The cellular and molecular mechanisms causing MN loss of function are only partially known. Recent advances in SMA research postulate the role of calpain protease regulating survival motor neuron (SMN) protein and the positive effect on SMA phenotype of treatment with calpain inhibitors. We analyzed the level of calpain pathway members in mice and human cellular SMA models. Results indicate an increase of calpain activity in SMN-reduced MNs. Spinal cord analysis of SMA mice treated with calpeptin, a calpain inhibitor, showed an increase of SMN, calpain, and its endogenous inhibitor calpastatin in MNs. Finally, in vitro calpeptin treatment prevented microtubule-associated protein 1A/1B-light chain 3 (LC3) increase in MNs neurites, indicating that calpain inhibition may reduce autophagosome accumulation in neuron prolongations, but not in soma. Thus, our results show that calpain activity is increased in SMA MNs and its inhibition may have a beneficial effect on SMA phenotype through the increase of SMN in spinal cord MNs.

脊髓性肌萎缩症（SMA）是由存活运动神经元1（SMN1）基因。SMA的特征是脊髓运动神经元（MN）变性，进行性骨骼肌萎缩和无力。导致MN功能丧失的细胞和分子机制只是部分已知。SMA研究的最新进展推测钙蛋白酶蛋白酶调节存活运动神经元（SMN）蛋白的作用以及钙蛋白酶抑制剂对SMA表型的积极作用。我们分析了小鼠和人类细胞SMA模型中钙蛋白酶途径成员的水平。结果表明在减少SMN的MN中钙蛋白酶活性增加。对用钙蛋白酶抑制剂（钙蛋白酶抑制剂）治疗的SMA小鼠进行的脊髓分析显示，MNs中SMN，钙蛋白酶及其内源性抑制剂钙蛋白酶抑制剂的含量增加。最后，体外钙蛋白酶抑制了MNs神经突中微管相关蛋白1A / 1B-轻链3（LC3）的增加，表明钙蛋白酶抑制可能会减少自噬体在神经元延长中的积累，但不能减少体细胞中的自噬。因此，我们的结果表明，钙蛋白酶的活性在SMA MNs中增加，并且其抑制作用可能通过在脊髓MNs中增加SMN而对SMA表型产生有益的影响。