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dc.contributor.authorSansa Zaragoza, Alba
dc.contributor.authorHidalgo, Iván
dc.contributor.authorMiralles, Maria P.
dc.contributor.authorFuente Ruiz, Sandra de la
dc.contributor.authorPerez‑Garcia, M. Jose
dc.contributor.authorMunell, Francina
dc.contributor.authorSoler i Tatché, Rosa Ma.
dc.contributor.authorGarcera, Ana
dc.description.abstractSpinal 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. Nevertheless, the mechanism by which SMN reduction in muscle contributes to SMA disease is not fully understood. Therefore, studies evaluating atrophy mechanisms in SMA muscles will contribute to strengthening current knowledge of the pathology. Here we propose to evaluate autophagy in SMA muscle, a pathway altered in myotube atrophy. We analized autophagy proteins and mTOR in muscle biopsies, fbroblasts, and lymphoblast cell lines from SMA patients and in gastrocnemius muscles from a severe SMA mouse model. Human MNs diferentiated from SMA and unafected control iPSCs were also included in the analysis of the autophagy. Muscle biopsies, fbro‑ blasts, and lymphoblast cell lines from SMA patients showed reduction of the autophagy marker LC3-II. In SMA mouse gastrocnemius, we observed lower levels of LC3-II, Beclin 1, and p62/SQSTM1 proteins at pre-symptomatic stage. mTOR phosphorylation at Ser2448 was decreased in SMA muscle cells. However, in mouse and human cultured SMA MNs mTOR phosphorylation and LC3-II levels were increased. These results suggest a diferential regulation in SMA of the autophagy process in muscle cells and MNs. Opposite changes in autophagy proteins and mTOR phosphorylation between muscle cells and neurons were observed. These diferences may refect a specifc response to SMN reduc‑ tion, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patientsca_ES
dc.description.sponsorshipThe authors wish to thank the consenting parents and patients. This work was supported by grants from Instituto de Salud Carlos III, Fondo de Inversiones Sanitarias, Unión Europea, Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” (PI17/00231, PI20/00098), AGAUR (2014 SGR 1087), and Fundació La Marató TV3 (73/C/2020). AG is a Serra Hunter Fellow from Generalitat de Catalunya, AS holds a fellowship from Universitat de Lleida and M.J.P-G was awarded the Marie-Curie fellowship (BP-B 00083). We thank Elaine Lilly, PhD, for English language revision of the manuscript.ca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofActa Neuropathologica Communications, 2021, núm. 9, 122ca_ES
dc.rightscc-by (c) Sansa et al., 2021ca_ES
dc.subjectSpinal muscular atrophyca_ES
dc.subjectSurvival motor neuronca_ES
dc.subjectNeuromuscular diseaseca_ES
dc.subjectHuman iPSCsca_ES
dc.titleSpinal Muscular Atrophy autophagy profle is tissue-dependent: diferential regulation between muscle and motoneuronsca_ES

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