MN degeneration are under study. Autophagy is a degradation pathway whose precise roles in neurodegeneration remain largely unknown, but abnormal autophagy has a central role in some neurodegenerative diseases, including MN disorders. The analysis of the autophagy response in SMA and its role in the development of the disease could be essential to understand the disease. In the present work, we describe an increase of autophagosomes and LC3-II protein in spinal cord MNs of severe SMA mouse model. A time-course experiment demonstrated increased LC3-II levels fromembryonic to postnatal stage, suggesting a deregulation of the autophagy process as the disease progressed. Using an in vitro model ofMN culture, we analyzed the effect of autophagy modulators on Smn (murine survival motor neuron) protein level. Results suggest that the inhibitors of the autophagy flux cause reduction ofSmn protein, whereas autophagy inducers increase the level of Smn protein inMNs. In order to evaluate other proteolytic systems involved to SMN degradation,we also studied the effect of the inhibition of the calcium-dependent protease, calpain, on Smn protein level. Our results demonstrate that calpain reduction increases Smn and LC3-II level in cultured MNs. Collectively, these results provide new insight into the role of autophagy and its modulation in SMN protein regulation.