Abstract
Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is caused by the loss of survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration and loss of spinal cord motoneurons (MNs), muscular atrophy, and weakness. SMN2 is the centromeric duplication of the SMN gene, whose numbers of copies determine the intracellular levels of SMN protein and define the disease onset and severity. It has been demonstrated that elevating SMN levels can be an important strategy in treating SMA and can be achieved by several mechanisms, including promotion of protein stability. SMN protein is a direct target of the calcium-dependent protease calpain and induces its proteolytic cleavage in muscle cells. In this study, we examined the involvement of calpain in SMN regulation on MNs. In vitro experiments showed that calpain activation induces SMN cleavage in CD1 and SMA mouse spinal cord MNs. Additionally, calpain 1 knockdown or inhibition increased SMN level and prevent neurite degeneration in these cells. We examined the effects of calpain inhibition on the phenotype of two severe SMA mouse models. Treatment with the calpain inhibitor, calpeptin, significantly improved the lifespan and motor function of these mice. Our observations show that calpain regulates SMN level in MNs and calpeptin administration improves SMA phenotype demonstrating the potential utility of calpain inhibitors in SMA therapy.
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder and the leading genetic cause of infant mortality [1, 2]
Calpains are involved in several muscle and neurodegenerative disorders, including SMA, and survival motor neuron (Smn) is a direct target of calpain cleavage in muscle tissue [24, 25]
In agreement with previous publications demonstrating that Smn located in the muscle cell is a proteolytic target of calpain [24, 25], we showed here that Smn protein level in MNs can be modulated by calpain
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder and the leading genetic cause of infant mortality [1, 2]. Our findings suggest that SMN protein can be regulated by calpain in spinal cord MNs and that calpeptin may be useful for the treatment of SMA. We observed a significantly increased Smn protein level in shCalp1 cells after 3 (1.30 ± 0.09, p < 0.05), 6 (1.69 ± 0.19, p < 0.005), and 9 (1.75 ± 0.46, p < 0.05) days of transduction, compared with the EV (Fig. 1a).
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