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SpinalMuscular Atrophy (SMA), a neurodegenerative disorder primarily affecting motoneurons (MNs), is caused
by the loss of the Survival Motor Neuron 1 (SMN1) gene and reduced levels of full-length survival motor neuron
(SMN) protein. The exact cellular/molecular mechanisms involved in SMN-induced 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.
Thisworkwas supported by grants fromInstituto de Salud Carlos III, Fondo de Investigaciones Sanitarias, Unión Europea, Fondo europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” (PI14/ 00060), Generalitat de Catalunya (SGR740). AP holds a fellowship from Comissionat d'Universitats i Recerca, Departament d'Innovació, Universitats i Empresa de la Generalitat de Catalunya i Fons Social Europeu, SA and SdF hold a fellowship from Universitat de Lleida, NB held a contract from Instituto de Salud Carlos III (PI11/01047). We thank Elaine Lilly, Ph.D., for English language revision of the manuscript. |
