{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:44:09Z","timestamp":1791384249981,"version":"4.3.3"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T00:00:00Z","timestamp":1625270400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T00:00:00Z","timestamp":1625270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient 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, fibroblasts, and lymphoblast cell lines from SMA patients and in gastrocnemius muscles from a severe SMA mouse model. Human MNs differentiated from SMA and unaffected control iPSCs were also included in the analysis of the autophagy. Muscle biopsies, fibroblasts, 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 differential 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 differences may reflect a specific\u00a0response to SMN reduction, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patients.<\/jats:p>","DOI":"10.1186\/s40478-021-01223-5","type":"journal-article","created":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T09:02:29Z","timestamp":1625302949000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons"],"prefix":"10.1186","volume":"9","author":[{"given":"Alba","family":"Sansa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Hidalgo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria P.","family":"Miralles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"de la Fuente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Jose","family":"Perez-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francina","family":"Munell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0528-3102","authenticated-orcid":false,"given":"Rosa M.","family":"Soler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Garcera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,3]]},"reference":[{"key":"1223_CR1","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1016\/S0140-6736(08)60921-6","volume":"371","author":"MR Lunn","year":"2008","unstructured":"Lunn MR, Wang CH (2008) Spinal muscular atrophy. Lancet 371:2120\u20132133","journal-title":"Lancet"},{"key":"1223_CR2","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1002\/ajmg.a.33474","volume":"152A","author":"TW Prior","year":"2010","unstructured":"Prior TW, Snyder PJ, Rink BD, Pearl DK, Pyatt RE, Mihal DC et al (2010) Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A 152A:1608\u20131616","journal-title":"Am J Med Genet A"},{"key":"1223_CR3","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","volume":"80","author":"S Lefebvre","year":"1995","unstructured":"Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155\u2013165","journal-title":"Cell"},{"key":"1223_CR4","doi-asserted-by":"publisher","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","volume":"96","author":"CL Lorson","year":"1999","unstructured":"Lorson CL, Hahnen E, Androphy EJ, Wirth B (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A 96:6307\u20136311","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1223_CR5","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1093\/hmg\/8.7.1177","volume":"8","author":"UR Monani","year":"1999","unstructured":"Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH et al (1999) A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 8:1177\u20131183","journal-title":"Hum Mol Genet"},{"key":"1223_CR6","doi-asserted-by":"publisher","first-page":"4334","DOI":"10.1093\/hmg\/ddr360","volume":"20","author":"CA Mutsaers","year":"2011","unstructured":"Mutsaers CA, Wishart TM, Lamont DJ, Riessland M, Schreml J, Comley LH et al (2011) Reversible molecular pathology of skeletal muscle in spinal muscular atrophy. Hum Mol Genet 20:4334\u20134344","journal-title":"Hum Mol Genet"},{"key":"1223_CR7","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1172\/JCI131989","volume":"130","author":"JK Kim","year":"2020","unstructured":"Kim JK, Jha NN, Feng Z, Faleiro MR, Chiriboga CA, Wei-Lapierre L et al (2020) Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models. J Clin Invest 130:1271\u20131287","journal-title":"J Clin Invest"},{"key":"1223_CR8","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.ceb.2009.12.002","volume":"22","author":"K Moreau","year":"2010","unstructured":"Moreau K, Luo S, Rubinsztein DC (2010) Cytoprotective roles for autophagy. Curr Opin Cell Biol 22:206\u2013211","journal-title":"Curr Opin Cell Biol"},{"key":"1223_CR9","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.cmet.2008.09.002","volume":"8","author":"G Dobrowolny","year":"2008","unstructured":"Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S et al (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8:425\u2013436","journal-title":"Cell Metab"},{"key":"1223_CR10","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1242\/dmm.010389","volume":"6","author":"P Bonaldo","year":"2013","unstructured":"Bonaldo P, Sandri M (2013) Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 6:25\u201339","journal-title":"Dis Model Mech"},{"key":"1223_CR11","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/j.cmet.2009.10.008","volume":"10","author":"E Masiero","year":"2009","unstructured":"Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M et al (2009) Autophagy is required to maintain muscle mass. Cell Metab 10:507\u2013515","journal-title":"Cell Metab"},{"key":"1223_CR12","doi-asserted-by":"publisher","first-page":"307","DOI":"10.4161\/auto.6.2.11137","volume":"6","author":"E Masiero","year":"2010","unstructured":"Masiero E, Sandri M (2010) Autophagy inhibition induces atrophy and myopathy in adult skeletal muscles. Autophagy 6:307\u2013309","journal-title":"Autophagy"},{"key":"1223_CR13","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.cell.2017.03.035","volume":"169","author":"RA Saxton","year":"2017","unstructured":"Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 169:361\u2013371","journal-title":"Cell"},{"key":"1223_CR14","doi-asserted-by":"publisher","first-page":"3963","DOI":"10.1074\/jbc.273.7.3963","volume":"273","author":"T Noda","year":"1998","unstructured":"Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273:3963\u20133966","journal-title":"J Biol Chem"},{"key":"1223_CR15","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1741-7015-7-14","volume":"7","author":"C Millino","year":"2009","unstructured":"Millino C, Fanin M, Vettori A, Laveder P, Mostacciuolo ML, Angelini C et al (2009) Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy. BMC Med 7:14","journal-title":"BMC Med"},{"key":"1223_CR16","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.phrs.2016.05.023","volume":"111","author":"YT Tseng","year":"2016","unstructured":"Tseng YT, Chen CS, Jong YJ, Chang FR, Lo YC (2016) Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt\/mTOR in experimental models of spinal muscular atrophy. Pharmacol Res 111:58\u201375","journal-title":"Pharmacol Res"},{"key":"1223_CR17","doi-asserted-by":"publisher","first-page":"e686","DOI":"10.1038\/cddis.2013.209","volume":"4","author":"A Garcera","year":"2013","unstructured":"Garcera A, Bahi N, Periyakaruppiah A, Arumugam S, Soler RM (2013) Survival motor neuron protein reduction deregulates autophagy in spinal cord motoneurons in vitro. Cell Death Dis 4:e686","journal-title":"Cell Death Dis"},{"key":"1223_CR18","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.mcn.2014.06.006","volume":"61","author":"SK Custer","year":"2014","unstructured":"Custer SK, Androphy EJ (2014) Autophagy dysregulation in cell culture and animals models of spinal muscular atrophy. Mol Cell Neurosci 61:133\u2013140","journal-title":"Mol Cell Neurosci"},{"key":"1223_CR19","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.expneurol.2016.06.032","volume":"283","author":"A Periyakaruppiah","year":"2016","unstructured":"Periyakaruppiah A, de la Fuente S, Arumugam S, Bahi N, Garcera A, Soler RM (2016) Autophagy modulators regulate survival motor neuron protein stability in motoneurons. Exp Neurol 283:287\u2013297","journal-title":"Exp Neurol"},{"key":"1223_CR20","doi-asserted-by":"publisher","first-page":"3008","DOI":"10.1172\/JCI95231","volume":"128","author":"N Rodriguez-Muela","year":"2018","unstructured":"Rodriguez-Muela N, Parkhitko A, Grass T, Gibbs RM, Norabuena EM, Perrimon N et al (2018) Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes. J Clin Invest 128:3008\u20133023","journal-title":"J Clin Invest"},{"key":"1223_CR21","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.1038\/s41419-017-0086-4","volume":"8","author":"A Piras","year":"2017","unstructured":"Piras A, Schiaffino L, Boido M, Valsecchi V, Guglielmotto M, De Amicis E et al (2017) Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy. Cell Death Dis 8:3223","journal-title":"Cell Death Dis"},{"key":"1223_CR22","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/S0960-8966(06)80015-5","volume":"2","author":"TL Munsat","year":"1992","unstructured":"Munsat TL, Davies KE (1992) International SMA consortium meeting (26\u201328 June 1992, Bonn, Germany). Neuromuscul Disord 2:423\u2013428","journal-title":"Neuromuscul Disord"},{"key":"1223_CR23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s00439-008-0598-1","volume":"125","author":"L Al\u00edas","year":"2009","unstructured":"Al\u00edas L, Bernal S, Fuentes-Prior P, Barcel\u00f3 MJ, Also E, Mart\u00ednez-Hern\u00e1ndez R et al (2009) Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Hum Genet 125:29\u201339","journal-title":"Hum Genet"},{"key":"1223_CR24","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s00415-005-0912-y","volume":"253","author":"I Cusc\u00f3","year":"2006","unstructured":"Cusc\u00f3 I, Barcel\u00f3 MJ, Rojas-Garc\u00eda R, Illa I, G\u00e1mez J, Cervera C et al (2006) SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings. J Neurol 253:21\u201325","journal-title":"J Neurol"},{"key":"1223_CR25","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1038\/ejhg.2011.89","volume":"19","author":"E Also-Rallo","year":"2011","unstructured":"Also-Rallo E, Al\u00edas L, Mart\u00ednez-Hern\u00e1ndez R, Caselles L, Barcel\u00f3 MJ, Baiget M et al (2011) Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability. Eur J Hum Genet 19:1059\u20131065","journal-title":"Eur J Hum Genet"},{"key":"1223_CR26","doi-asserted-by":"publisher","first-page":"6626","DOI":"10.1038\/ncomms7626","volume":"6","author":"ZW Du","year":"2015","unstructured":"Du ZW, Chen H, Liu H, Lu J, Qian K, Huang CL et al (2015) Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat Commun 6:6626","journal-title":"Nat Commun"},{"key":"1223_CR27","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41419-020-2688-5","volume":"11","author":"S de la Fuente","year":"2020","unstructured":"de la Fuente S, Sansa A, Hidalgo I, Vivancos N, Romero-Guevara R, Garcera A et al (2020) Calpain system is altered in survival motor neuron-reduced cells from in vitro and in vivo spinal muscular atrophy models. Cell Death Dis 11:487","journal-title":"Cell Death Dis"},{"key":"1223_CR28","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1111\/j.1471-4159.2009.06278.x","volume":"110","author":"M Gou-Fabregas","year":"2009","unstructured":"Gou-Fabregas M, Garcera A, Mincheva S, Perez-Garcia MJ, Comella JX, Soler RM (2009) Specific vulnerability of mouse spinal cord motoneurons to membrane depolarization. J Neurochem 110:1842\u20131854","journal-title":"J Neurochem"},{"key":"1223_CR29","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676\u2013682","journal-title":"Nat Methods"},{"key":"1223_CR30","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1091\/mbc.e03-09-0704","volume":"15","author":"N Mizushima","year":"2004","unstructured":"Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101\u20131111","journal-title":"Mol Biol Cell"},{"key":"1223_CR31","doi-asserted-by":"publisher","first-page":"318","DOI":"10.4161\/auto.2984","volume":"2","author":"T Fukuda","year":"2006","unstructured":"Fukuda T, Roberts A, Ahearn M, Zaal K, Ralston E, Plotz PH et al (2006) Autophagy and lysosomes in Pompe disease. Autophagy 2:318\u2013320","journal-title":"Autophagy"},{"key":"1223_CR32","doi-asserted-by":"publisher","first-page":"2552","DOI":"10.1093\/hmg\/ddn156","volume":"17","author":"S Kariya","year":"2008","unstructured":"Kariya S, Park GH, Maeno-Hikichi Y, Leykekhman O, Lutz C, Arkovitz MS et al (2008) Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet 17:2552\u20132569","journal-title":"Hum Mol Genet"},{"key":"1223_CR33","doi-asserted-by":"publisher","first-page":"28846","DOI":"10.1038\/srep28846","volume":"6","author":"MO Deguise","year":"2016","unstructured":"Deguise MO, Boyer JG, McFall ER, Yazdani A, De Repentigny Y, Kothary R (2016) Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy. Sci Rep 6:28846","journal-title":"Sci Rep"},{"key":"1223_CR34","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/cdd.2010.191","volume":"18","author":"R Kang","year":"2011","unstructured":"Kang R, Zeh HJ, Lotze MT, Tang D (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18:571\u2013580","journal-title":"Cell Death Differ"},{"key":"1223_CR35","doi-asserted-by":"publisher","first-page":"784","DOI":"10.4161\/auto.6.6.12510","volume":"6","author":"KB Larsen","year":"2010","unstructured":"Larsen KB, Lamark T, \u00d8vervatn A, Harneshaug I, Johansen T, Bj\u00f8rk\u00f8y G (2010) A reporter cell system to monitor autophagy based on p62\/SQSTM1. Autophagy 6:784\u2013793","journal-title":"Autophagy"},{"key":"1223_CR36","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0076-6879(08)03612-4","volume":"452","author":"G Bj\u00f8rk\u00f8y","year":"2009","unstructured":"Bj\u00f8rk\u00f8y G, Lamark T, Pankiv S, \u00d8vervatn A, Brech A, Johansen T (2009) Monitoring autophagic degradation of p62\/SQSTM1. Methods Enzymol 452:181\u2013197","journal-title":"Methods Enzymol"},{"key":"1223_CR37","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.mam.2006.08.005","volume":"27","author":"EL Eskelinen","year":"2006","unstructured":"Eskelinen EL (2006) Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol Aspects Med 27:495\u2013502","journal-title":"Mol Aspects Med"},{"key":"1223_CR38","doi-asserted-by":"publisher","first-page":"17657","DOI":"10.1074\/jbc.M201142200","volume":"277","author":"TH Reynolds","year":"2002","unstructured":"Reynolds TH, Bodine SC, Lawrence JC (2002) Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J Biol Chem 277:17657\u201317662","journal-title":"J Biol Chem"},{"key":"1223_CR39","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.molmed.2012.11.002","volume":"19","author":"G Hamilton","year":"2013","unstructured":"Hamilton G, Gillingwater TH (2013) Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med 19:40\u201350","journal-title":"Trends Mol Med"},{"key":"1223_CR40","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.cmet.2013.03.015","volume":"17","author":"P Castets","year":"2013","unstructured":"Castets P, Lin S, Rion N, Di Fulvio S, Romanino K, Guridi M et al (2013) Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy. Cell Metab 17:731\u2013744","journal-title":"Cell Metab"},{"key":"1223_CR41","doi-asserted-by":"publisher","first-page":"3667","DOI":"10.1093\/hmg\/ddr288","volume":"20","author":"DY Kwon","year":"2011","unstructured":"Kwon DY, Motley WW, Fischbeck KH, Burnett BG (2011) Increasing expression and decreasing degradation of SMN ameliorate the spinal muscular atrophy phenotype in mice. Hum Mol Genet 20:3667\u20133677","journal-title":"Hum Mol Genet"},{"key":"1223_CR42","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1128\/MCB.01262-08","volume":"29","author":"BG Burnett","year":"2009","unstructured":"Burnett BG, Mu\u00f1oz E, Tandon A, Kwon DY, Sumner CJ, Fischbeck KH (2009) Regulation of SMN protein stability. Mol Cell Biol 29:1107\u20131115","journal-title":"Mol Cell Biol"},{"key":"1223_CR43","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.biochi.2019.07.014","volume":"166","author":"D Taillandier","year":"2019","unstructured":"Taillandier D, Polge C (2019) Skeletal muscle atrogenes: from rodent models to human pathologies. Biochimie 166:251\u2013269","journal-title":"Biochimie"},{"key":"1223_CR44","doi-asserted-by":"publisher","first-page":"2862","DOI":"10.3390\/ijms21082862","volume":"21","author":"KW Kim","year":"2020","unstructured":"Kim KW, Cho HJ, Khaliq SA, Son KH, Yoon MS (2020) Comparative analyses of mTOR\/Akt and muscle atrophy-related signaling in aged respiratory and gastrocnemius muscles. Int J Mol Sci 21:2862","journal-title":"Int J Mol Sci"},{"key":"1223_CR45","doi-asserted-by":"publisher","first-page":"e144","DOI":"10.1038\/cddis.2011.29","volume":"2","author":"R Russo","year":"2011","unstructured":"Russo R, Berliocchi L, Adornetto A, Varano GP, Cavaliere F, Nucci C et al (2011) Calpain-mediated cleavage of Beclin-1 and autophagy deregulation following retinal ischemic injury in vivo. Cell Death Dis 2:e144","journal-title":"Cell Death Dis"},{"key":"1223_CR46","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1007\/s13238-010-0048-4","volume":"1","author":"Y Zhu","year":"2010","unstructured":"Zhu Y, Zhao L, Liu L, Gao P, Tian W, Wang X et al (2010) Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis. Protein Cell 1:468\u2013477","journal-title":"Protein Cell"},{"key":"1223_CR47","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1093\/hmg\/ddx418","volume":"27","author":"L Sheng","year":"2018","unstructured":"Sheng L, Wan B, Feng P, Sun J, Rigo F, Bennett CF et al (2018) Downregulation of Survivin contributes to cell-cycle arrest during postnatal cardiac development in a severe spinal muscular atrophy mouse model. Hum Mol Genet 27:486\u2013498","journal-title":"Hum Mol Genet"},{"key":"1223_CR48","doi-asserted-by":"publisher","first-page":"e39113","DOI":"10.1371\/journal.pone.0039113","volume":"7","author":"D Sareen","year":"2012","unstructured":"Sareen D, Ebert AD, Heins BM, McGivern JV, Ornelas L, Svendsen CN (2012) Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy. PLoS ONE 7:e39113","journal-title":"PLoS ONE"},{"key":"1223_CR49","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.neuroscience.2016.11.017","volume":"341","author":"K Switon","year":"2017","unstructured":"Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J (2017) Molecular neurobiology of mTOR. Neuroscience 341:112\u2013153","journal-title":"Neuroscience"},{"key":"1223_CR50","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1038\/ncb1101-1014","volume":"3","author":"SC Bodine","year":"2001","unstructured":"Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R et al (2001) Akt\/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3:1014\u20131019","journal-title":"Nat Cell Biol"},{"key":"1223_CR51","doi-asserted-by":"publisher","first-page":"162","DOI":"10.3389\/fnmol.2020.00162","volume":"13","author":"P Castets","year":"2020","unstructured":"Castets P, Ham DJ, R\u00fcegg MA (2020) The TOR pathway at the neuromuscular junction: more than a metabolic player? Front Mol Neurosci 13:162","journal-title":"Front Mol Neurosci"},{"key":"1223_CR52","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s40478-019-0806-3","volume":"7","author":"WA Rehorst","year":"2019","unstructured":"Rehorst WA, Thelen MP, Nolte H, T\u00fcrk C, Cirak S, Peterson JM et al (2019) Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy. Acta Neuropathol Commun 7:154","journal-title":"Acta Neuropathol Commun"},{"key":"1223_CR53","doi-asserted-by":"publisher","first-page":"412","DOI":"10.4161\/auto.7.4.14541","volume":"7","author":"X Zhang","year":"2011","unstructured":"Zhang X, Li L, Chen S, Yang D, Wang Y, Wang Z et al (2011) Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7:412\u2013425","journal-title":"Autophagy"},{"key":"1223_CR54","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/nchembio.1563","volume":"10","author":"SJ Barmada","year":"2014","unstructured":"Barmada SJ, Serio A, Arjun A, Bilican B, Daub A, Ando DM et al (2014) Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol 10:677\u2013685","journal-title":"Nat Chem Biol"},{"key":"1223_CR55","doi-asserted-by":"publisher","first-page":"2294","DOI":"10.1101\/gad.1830709","volume":"23","author":"C Hetz","year":"2009","unstructured":"Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R et al (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294\u20132306","journal-title":"Genes Dev"},{"key":"1223_CR56","doi-asserted-by":"publisher","first-page":"958","DOI":"10.4161\/auto.6.7.13042","volume":"6","author":"V Crippa","year":"2010","unstructured":"Crippa V, Carra S, Rusmini P, Sau D, Bolzoni E, Bendotti C et al (2010) A role of small heat shock protein B8 (HspB8) in the autophagic removal of misfolded proteins responsible for neurodegenerative diseases. Autophagy 6:958\u2013960","journal-title":"Autophagy"},{"key":"1223_CR57","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1750-1326-5-26","volume":"5","author":"JH Fox","year":"2010","unstructured":"Fox JH, Connor T, Chopra V, Dorsey K, Kama JA, Bleckmann D et al (2010) The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6\/2 mouse model of Huntington\u2019s disease. Mol Neurodegener 5:26","journal-title":"Mol Neurodegener"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-021-01223-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-021-01223-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-021-01223-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,3]],"date-time":"2021-07-03T09:14:33Z","timestamp":1625303673000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-021-01223-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,3]]},"references-count":57,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1223"],"URL":"https:\/\/doi.org\/10.1186\/s40478-021-01223-5","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,3]]},"assertion":[{"value":"3 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All protocols regarding human samples were approved by the Hospital Vall d\u2019Hebron (Barcelona) and Hospital de la Santa Creu i Sant Pau (Barcelona) in agreement with the guidelines specified by the Hospital Ethics Committee. All procedures with mice were done in accordance with the Spanish Council on Animal Care guidelines and approved by the University of Lleida Advisory Committee on Animal Services (CEEA02- 01\/17).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"122"}}