Autophagy modulators regulate survival motor neuron protein stability in motoneurons
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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.
Is part ofExperimental Neurology, 2016, vol. 283, p. 287–297
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Spinal Muscular Atrophy autophagy profle is tissue-dependent: diferential regulation between muscle and motoneurons Sansa Zaragoza, Alba; Hidalgo, Iván; Miralles, Maria P.; Fuente Ruiz, Sandra de la; Pérez García, María José; Munell, Francina; Soler i Tatché, Rosa Ma.; Garcera, Ana (BioMed Central, 2021)Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and defcient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. ...
Regulation of survival motor neuron protein by the nuclear factor-kappa B pathway in mouse spinal cord motoneurons Arumugam, Saravanan; Tasheva, Stefka Mincheva; Periyakaruppiah, Ambika; Fuente Ruiz, Sandra de la; Soler i Tatché, Rosa Ma.; Garcera, Ana (Springer Verlag, 2017-08-14)Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease ...
Calpain Inhibition Increases SMN Protein in Spinal Cord Motoneurons and Ameliorates the Spinal Muscular Atrophy Phenotype in Mice Fuente Ruiz, Sandra de la; Sansa Zaragoza, Alba; Periyakaruppiah, Ambika; Garcera, Ana; Soler i Tatché, Rosa Ma. (Springer Verlag, 2018)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), ...