Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models

被引:15
作者
de la Fuente, Sandra [1 ]
Sansa, Alba [1 ]
Hidalgo, Ivan [1 ]
Vivancos, Nuria [1 ]
Romero-Guevara, Ricardo [2 ]
Garcera, Ana [1 ]
Soler, Rosa M. [1 ]
机构
[1] Univ Lleida IRBLleida, Dept Expt Med, Neuronal Signaling Unit, Rovira Roure 80, Lleida 25198, Spain
[2] Univ Lleida IRBLleida, Dept Expt Med, Metab Physiopathol Grp, Lleida, Spain
关键词
SINGLE NUCLEOTIDE; GENE-PRODUCT; AUTOPHAGY; SMN; DISEASE; PROTEIN; INHIBITION; MTOR; MOTONEURONS; HOMEOSTASIS;
D O I
10.1038/s41419-020-2688-5
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by loss of thesurvival 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.
引用
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页数:15
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