{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:19:07Z","timestamp":1792124347308,"version":"4.4.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T00:00:00Z","timestamp":1710201600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T00:00:00Z","timestamp":1710201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Myelin Repair Foundation and the European Regional Development Fund"},{"DOI":"10.13039\/501100010275","name":"German Society for Muscular Diseases","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010275","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100017590","name":"Universit\u00e4tsklinikum Essen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017590","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (<jats:italic>SMN1<\/jats:italic>) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers.\u00a0To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1\u20133 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1\u20133) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.<\/jats:p>","DOI":"10.1007\/s00401-024-02709-x","type":"journal-article","created":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T08:01:39Z","timestamp":1710230499000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy"],"prefix":"10.1007","volume":"147","author":[{"given":"Andreas","family":"Roos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2506-1080","authenticated-orcid":false,"given":"Linda-Isabell","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Hansmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Hezel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Schahin","family":"Salmanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela Della","family":"Marina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"K\u00f6lbel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kleinschnitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Schara-Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Leo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Hagenacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,12]]},"reference":[{"key":"2709_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12206696","author":"M Beaudin","year":"2023","unstructured":"Beaudin M, Kamali T, Tang W, Hagerman KA, Dunaway Young S, Ghiglieri L et al (2023) Cerebrospinal fluid proteomic changes after nusinersen in patients with spinal muscular atrophy. J Clin Med. https:\/\/doi.org\/10.3390\/jcm12206696","journal-title":"J Clin Med"},{"key":"2709_CR2","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1021\/pr050300l","volume":"5","author":"SJ Callister","year":"2006","unstructured":"Callister SJ, Barry RC, Adkins JN, Johnson ET, Qian WJ, Webb-Robertson BJ et al (2006) Normalization approaches for removing systematic biases associated with mass spectrometry and label-free proteomics. J Proteome Res 5:277\u2013286. https:\/\/doi.org\/10.1021\/pr050300l","journal-title":"J Proteome Res"},{"key":"2709_CR3","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1212\/WNL.0000000000002445","volume":"86","author":"CA Chiriboga","year":"2016","unstructured":"Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC et al (2016) Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 86:890\u2013897. https:\/\/doi.org\/10.1212\/WNL.0000000000002445","journal-title":"Neurology"},{"key":"2709_CR4","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1006\/nbdi.1996.0010","volume":"3","author":"TO Crawford","year":"1996","unstructured":"Crawford TO, Pardo CA (1996) The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis 3:97\u2013110. https:\/\/doi.org\/10.1006\/nbdi.1996.0010","journal-title":"Neurobiol Dis"},{"key":"2709_CR5","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12816","volume":"48","author":"D D'Amico","year":"2022","unstructured":"D\u2019Amico D, Biondi O, Januel C, Bezier C, Sapaly D, Clerc Z et al (2022) Activating ATF6 in spinal muscular atrophy promotes SMN expression and motor neuron survival through the IRE1alpha-XBP1 pathway. Neuropathol Appl Neurobiol 48:e12816. https:\/\/doi.org\/10.1111\/nan.12816","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2709_CR6","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/j.nmd.2019.09.007","volume":"29","author":"DC De Vivo","year":"2019","unstructured":"De Vivo DC, Bertini E, Swoboda KJ, Hwu WL, Crawford TO, Finkel RS et al (2019) Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the Phase 2 nurture study. Neuromuscul Disord 29:842\u2013856. https:\/\/doi.org\/10.1016\/j.nmd.2019.09.007","journal-title":"Neuromuscul Disord"},{"key":"2709_CR7","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1002\/acn3.51625","volume":"9","author":"B De Wel","year":"2022","unstructured":"De Wel B, De Schaepdryver M, Poesen K, Claeys KG (2022) Biochemical and clinical biomarkers in adult SMA 3\u20134 patients treated with nusinersen for 22\u00a0months. Ann Clin Transl Neurol 9:1241\u20131251. https:\/\/doi.org\/10.1002\/acn3.51625","journal-title":"Ann Clin Transl Neurol"},{"key":"2709_CR8","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1007\/s40265-020-01410-z","volume":"80","author":"S Dhillon","year":"2020","unstructured":"Dhillon S (2020) Risdiplam: first approval. Drugs 80:1853\u20131858. https:\/\/doi.org\/10.1007\/s40265-020-01410-z","journal-title":"Drugs"},{"key":"2709_CR9","doi-asserted-by":"publisher","first-page":"3034","DOI":"10.1111\/jcmm.14939","volume":"24","author":"I Faravelli","year":"2020","unstructured":"Faravelli I, Meneri M, Saccomanno D, Velardo D, Abati E, Gagliardi D et al (2020) Nusinersen treatment and cerebrospinal fluid neurofilaments: an explorative study on spinal muscular atrophy type 3 patients. J Cell Mol Med 24:3034\u20133039. https:\/\/doi.org\/10.1111\/jcmm.14939","journal-title":"J Cell Mol Med"},{"key":"2709_CR10","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/nn.3903","volume":"18","author":"A Filezac de L'Etang","year":"2015","unstructured":"Filezac de L\u2019Etang A, Maharjan N, Cordeiro Brana M, Ruegsegger C, Rehmann R, Goswami A et al (2015) Marinesco-Sjogren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS. Nat Neurosci 18:227\u2013238. https:\/\/doi.org\/10.1038\/nn.3903","journal-title":"Nat Neurosci"},{"key":"2709_CR11","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","volume":"377","author":"RS Finkel","year":"2017","unstructured":"Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J et al (2017) Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377:1723\u20131732. https:\/\/doi.org\/10.1056\/NEJMoa1702752","journal-title":"N Engl J Med"},{"key":"2709_CR12","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1016\/j.neurol.2020.03.020","volume":"176","author":"F Francini-Pesenti","year":"2020","unstructured":"Francini-Pesenti F, Vitturi N, Tresso S, Soraru G (2020) Metabolic alterations in spinal and bulbar muscular atrophy. Rev Neurol (Paris) 176:780\u2013787. https:\/\/doi.org\/10.1016\/j.neurol.2020.03.020","journal-title":"Rev Neurol (Paris)"},{"key":"2709_CR13","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1093\/hmg\/dds483","volume":"22","author":"JD Gumerson","year":"2013","unstructured":"Gumerson JD, Davis CS, Kabaeva ZT, Hayes JM, Brooks SV, Michele DE (2013) Muscle-specific expression of LARGE restores neuromuscular transmission deficits in dystrophic LARGE(myd) mice. Hum Mol Genet 22:757\u2013768. https:\/\/doi.org\/10.1093\/hmg\/dds483","journal-title":"Hum Mol Genet"},{"key":"2709_CR14","doi-asserted-by":"publisher","first-page":"45","DOI":"10.3389\/fneur.2020.00045","volume":"11","author":"N Hensel","year":"2020","unstructured":"Hensel N, Kubinski S, Claus P (2020) The need for SMN-independent treatments of spinal muscular atrophy (SMA) to complement SMN-enhancing drugs. Front Neurol 11:45. https:\/\/doi.org\/10.3389\/fneur.2020.00045","journal-title":"Front Neurol"},{"key":"2709_CR15","doi-asserted-by":"publisher","first-page":"3487","DOI":"10.1021\/pr3000249","volume":"11","author":"CD Kelstrup","year":"2012","unstructured":"Kelstrup CD, Young C, Lavallee R, Nielsen ML, Olsen JV (2012) Optimized fast and sensitive acquisition methods for shotgun proteomics on a quadrupole orbitrap mass spectrometer. J Proteome Res 11:3487\u20133497. https:\/\/doi.org\/10.1021\/pr3000249","journal-title":"J Proteome Res"},{"key":"2709_CR16","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1111\/cge.14053","volume":"100","author":"U Kotecha","year":"2021","unstructured":"Kotecha U, Mistri M, Shah N, Shah PS, Gupta VA (2021) Bi-allelic loss of function variants in GOLGA2 are associated with a complex neurological phenotype: Report of a second family. Clin Genet 100:748\u2013751. https:\/\/doi.org\/10.1111\/cge.14053","journal-title":"Clin Genet"},{"key":"2709_CR17","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. https:\/\/doi.org\/10.1016\/0092-8674(95)90460-3","journal-title":"Cell"},{"key":"2709_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/cells11030558","author":"M Leo","year":"2022","unstructured":"Leo M, Schmitt LI, Fleischer M, Steffen R, Osswald C, Kleinschnitz C et al (2022) Induction of survival of motor neuron (SMN) protein deficiency in spinal astrocytes by small interfering RNA as an In Vitro model of spinal muscular atrophy. Cells. https:\/\/doi.org\/10.3390\/cells11030558","journal-title":"Cells"},{"key":"2709_CR19","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1093\/hmg\/9.2.259","volume":"9","author":"CL Lorson","year":"2000","unstructured":"Lorson CL, Androphy EJ (2000) An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 9:259\u2013265. https:\/\/doi.org\/10.1093\/hmg\/9.2.259","journal-title":"Hum Mol Genet"},{"key":"2709_CR20","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1097\/NEN.0000000000000065","volume":"73","author":"KG Meilleur","year":"2014","unstructured":"Meilleur KG, Zukosky K, Medne L, Fequiere P, Powell-Hamilton N, Winder TL et al (2014) Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by large mutations. J Neuropathol Exp Neurol 73:425\u2013441. https:\/\/doi.org\/10.1097\/NEN.0000000000000065","journal-title":"J Neuropathol Exp Neurol"},{"key":"2709_CR21","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1706198","volume":"377","author":"JR Mendell","year":"2017","unstructured":"Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW et al (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377:1713\u20131722. https:\/\/doi.org\/10.1056\/NEJMoa1706198","journal-title":"N Engl J Med"},{"key":"2709_CR22","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1056\/NEJMoa1710504","volume":"378","author":"E Mercuri","year":"2018","unstructured":"Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM et al (2018) Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 378:625\u2013635. https:\/\/doi.org\/10.1056\/NEJMoa1710504","journal-title":"N Engl J Med"},{"key":"2709_CR23","doi-asserted-by":"publisher","first-page":"865","DOI":"10.4103\/1673-5374.297087","volume":"16","author":"SP Niu","year":"2021","unstructured":"Niu SP, Zhang YJ, Han N, Yin XF, Zhang DY, Kou YH (2021) Identification of four differentially expressed genes associated with acute and chronic spinal cord injury based on bioinformatics data. Neural Regen Res 16:865\u2013870. https:\/\/doi.org\/10.4103\/1673-5374.297087","journal-title":"Neural Regen Res"},{"key":"2709_CR24","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1007\/s00415-019-09389-8","volume":"266","author":"B Olsson","year":"2019","unstructured":"Olsson B, Alberg L, Cullen NC, Michael E, Wahlgren L, Kroksmark AK et al (2019) NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol 266:2129\u20132136. https:\/\/doi.org\/10.1007\/s00415-019-09389-8","journal-title":"J Neurol"},{"key":"2709_CR25","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.jns.2005.03.015","volume":"233","author":"A Petzold","year":"2005","unstructured":"Petzold A (2005) Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J Neurol Sci 233:183\u2013198. https:\/\/doi.org\/10.1016\/j.jns.2005.03.015","journal-title":"J Neurol Sci"},{"key":"2709_CR26","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.1111\/ene.15331","volume":"29","author":"DC Schorling","year":"2022","unstructured":"Schorling DC, Kolbel H, Hentschel A, Pechmann A, Meyer N, Wirth B et al (2022) Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy. Eur J Neurol 29:2084\u20132096. https:\/\/doi.org\/10.1111\/ene.15331","journal-title":"Eur J Neurol"},{"key":"2709_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3233\/JND-190424","volume":"7","author":"DC Schorling","year":"2020","unstructured":"Schorling DC, Pechmann A, Kirschner J (2020) Advances in treatment of spinal muscular atrophy\u2014new phenotypes, new challenges, new implications for care. J Neuromuscul Dis 7:1\u201313. https:\/\/doi.org\/10.3233\/JND-190424","journal-title":"J Neuromuscul Dis"},{"key":"2709_CR28","doi-asserted-by":"publisher","DOI":"10.3390\/jpm10030075","author":"P Smeriglio","year":"2020","unstructured":"Smeriglio P, Langard P, Querin G, Biferi MG (2020) The identification of novel biomarkers is required to improve adult SMA patient stratification, diagnosis and treatment. J Pers Med. https:\/\/doi.org\/10.3390\/jpm10030075","journal-title":"J Pers Med"},{"key":"2709_CR29","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1002\/acn3.51336","volume":"8","author":"C Spicer","year":"2021","unstructured":"Spicer C, Lu CH, Catapano F, Scoto M, Zaharieva I, Malaspina A et al (2021) The altered expression of neurofilament in mouse models and patients with spinal muscular atrophy. Ann Clin Transl Neurol 8:866\u2013876. https:\/\/doi.org\/10.1002\/acn3.51336","journal-title":"Ann Clin Transl Neurol"},{"key":"2709_CR30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20215397","author":"A Totzeck","year":"2019","unstructured":"Totzeck A, Stolte B, Kizina K, Bolz S, Schlag M, Thimm A et al (2019) Neurofilament heavy chain and tau protein are not elevated in cerebrospinal fluid of adult patients with spinal muscular atrophy during loading with nusinersen. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms20215397","journal-title":"Int J Mol Sci"},{"key":"2709_CR31","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a018309","author":"A Yuan","year":"2017","unstructured":"Yuan A, Rao MV, Veeranna NRA (2017) Neurofilaments and neurofilament proteins in health and disease. Cold Spring Harb Perspect Biol. https:\/\/doi.org\/10.1101\/cshperspect.a018309","journal-title":"Cold Spring Harb Perspect Biol"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-024-02709-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-024-02709-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-024-02709-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T08:02:41Z","timestamp":1710230561000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-024-02709-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,12]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,6]]}},"alternative-id":["2709"],"URL":"https:\/\/doi.org\/10.1007\/s00401-024-02709-x","relation":{},"ISSN":["0001-6322","1432-0533"],"issn-type":[{"value":"0001-6322","type":"print"},{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,12]]},"assertion":[{"value":"16 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 February 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was moreover reviewed and approved by the institutional ethics board of the University Medicine Essen (No. 19\u20139011-BO).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"This study was conducted under the animal welfare guidelines of the University Duisburg Essen, Germany. Furthermore, the use of the SMA mouse model was approved by the State Agency for Nature, Environment and Consumer Protection (LANUV) in North Rhine-Westphalia (reference number 81.02.04.2020.A335).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving human and\/or animal participants"}}],"article-number":"53"}}