{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:30:46Z","timestamp":1760059846805,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health \u201cRicerca Corrente 2025-2027\u201d"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects motor neurons of people, leading to death. This pathology can be caused by mutations in different genes, including superoxide dismutase 1 (SOD1). Previous studies have pointed out the presence of two transcripts of SOD1, a short one and a long one. The aim of this study was the investigation of these two transcripts both in the SH-SY5Y cell line and in patients\u2019 peripheral blood mononuclear cells. We found that the shortest SOD1 transcript is upregulated under stress conditions in both the cellular model and the patients\u2019 cells. Moreover, we found a potential correlation between the short SOD1 transcript and the severity of the pathology, which also correlates with the age of patients. No correlation was found between SOD1 transcripts and the progression of the disease. These data suggest a toxic effect of short SOD1 transcripts in ALS patients, by affecting the severity of the pathology making it a possible biomarker for this disease. Interestingly, our data suggest that a short SOD1 transcript does not influence and drive disease progression. The finding of a biomarker will have suitable implications as indicators of disease severity and from the perspective of drug development.<\/jats:p>","DOI":"10.3390\/ijms26146788","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T15:01:05Z","timestamp":1752591665000},"page":"6788","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of SOD1 Transcript Variants on Amyotrophic Lateral Sclerosis Severity"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9461-756X","authenticated-orcid":false,"given":"Matteo","family":"Bordoni","sequence":"first","affiliation":[{"name":"Cellular Models and Neuroepigenetics Section, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6703-1755","authenticated-orcid":false,"given":"Eveljn","family":"Scarian","sequence":"additional","affiliation":[{"name":"Cellular Models and Neuroepigenetics Section, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1410-5510","authenticated-orcid":false,"given":"Camilla","family":"Viola","sequence":"additional","affiliation":[{"name":"Cellular Models and Neuroepigenetics Section, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"},{"name":"Department of Brain and Behavioral Sciences, University of Pavia, Via Agostino Bassi 21, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7608-3306","authenticated-orcid":false,"given":"Francesca","family":"Dragoni","sequence":"additional","affiliation":[{"name":"Molecular Biology and Transcriptomics Section, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7834-0342","authenticated-orcid":false,"given":"Rosalinda","family":"Di Gerlando","sequence":"additional","affiliation":[{"name":"Molecular Biology and Transcriptomics Section, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"},{"name":"Department of Biology and Biotechnology \u201cL. Spallanzani\u201d, University of Pavia, Via Adolfo Ferrata 9, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5799-7732","authenticated-orcid":false,"given":"Bartolo","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Golgi Cenci Foundation, Corso S. Martino 10, 20081 Abbiategrasso, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Diamanti","sequence":"additional","affiliation":[{"name":"Neuroncology and Neuroinflammation Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-6907","authenticated-orcid":false,"given":"Stella","family":"Gagliardi","sequence":"additional","affiliation":[{"name":"Molecular Biology and Transcriptomics Section, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-0612","authenticated-orcid":false,"given":"Orietta","family":"Pansarasa","sequence":"additional","affiliation":[{"name":"Cellular Models and Neuroepigenetics Section, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1097\/WCO.0000000000001097","article-title":"The challenge of amyotrophic lateral sclerosis descriptive epidemiology: To estimate low incidence rates across complex phenotypes in different geographic areas","volume":"35","author":"Logroscino","year":"2022","journal-title":"Curr. Opin. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.chest.2018.06.035","article-title":"Respiratory Failure in Amyotrophic Lateral Sclerosis","volume":"155","author":"Niedermeyer","year":"2019","journal-title":"Chest"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120156","DOI":"10.1016\/j.lfs.2021.120156","article-title":"The panoramic view of amyotrophic lateral sclerosis: A fatal intricate neurological disorder","volume":"288","author":"Dhasmana","year":"2022","journal-title":"Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1136\/jnnp-2016-315018","article-title":"Genetic epidemiology of amyotrophic lateral sclerosis: A systematic review and meta-analysis","volume":"88","author":"Zou","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Vidovic, M., M\u00fcschen, L.H., Brakemeier, S., Machetanz, G., Naumann, M., and Castro-Gomez, S. (2023). Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis. Cells, 12.","DOI":"10.3390\/cells12050736"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1097\/WCO.0000000000000864","article-title":"Amyotrophic lateral sclerosis: Update on clinical management","volume":"33","author":"Norris","year":"2020","journal-title":"Curr. Opin. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/362059a0","article-title":"Mutations in Cu\/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis","volume":"362","author":"Rosen","year":"1993","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1136\/jnnp-2021-327520","article-title":"De novo mutations in SOD1 are a cause of ALS","volume":"93","author":"Oh","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Garcia, C., Vidal-Taboada, J.M., Syriani, E., Salvado, M., Morales, M., and Gamez, J. (2019). Haplotype Analysis of the First A4V-SOD1 Spanish Family: Two Separate Founders or a Single Common Founder?. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.01109"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0891-5849(02)00905-X","article-title":"Superoxide dismutase multigene family: A comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression","volume":"33","author":"Zelko","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature20413","article-title":"Decoding ALS: From genes to mechanism","volume":"539","author":"Taylor","year":"2016","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Fang, T., Je, G., Pacut, P., Keyhanian, K., Gao, J., and Ghasemi, M. (2022). Gene Therapy in Amyotrophic Lateral Sclerosis. Cells, 11.","DOI":"10.3390\/cells11132066"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e28771","DOI":"10.1097\/MD.0000000000028771","article-title":"The G41D mutation in SOD1-related amyotrophic lateral sclerosis exhibits phenotypic heterogeneity among individuals: A case report and literature review","volume":"101","author":"Zhao","year":"2022","journal-title":"Medicine"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Scarian, E., Bordoni, M., Fantini, V., Jacchetti, E., Raimondi, M.T., Diamanti, L., Carelli, S., Cereda, C., and Pansarasa, O. (2022). Patients\u2019 Stem Cells Differentiation in a 3D Environment as a Promising Experimental Tool for the Study of Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105344"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pansarasa, O., Bordoni, M., Diamanti, L., Sproviero, D., Gagliardi, S., and Cereda, C. (2018). SOD1 in Amyotrophic Lateral Sclerosis: \u201cAmbivalent\u201d Behavior Connected to the Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051345"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pansarasa, O., Garofalo, M., Scarian, E., Dragoni, F., Garau, J., Di Gerlando, R., Diamanti, L., Bordoni, M., and Gagliardi, S. (2022). Biomarkers in Human Peripheral Blood Mononuclear Cells: The State of the Art in Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052580"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3620","DOI":"10.1073\/pnas.1312245111","article-title":"Intercellular propagated misfolding of wild-type Cu\/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms","volume":"111","author":"Grad","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s00401-015-1514-0","article-title":"Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways","volume":"131","author":"Ayers","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3744","DOI":"10.1074\/jbc.RA118.004825","article-title":"CNS-derived extracellular vesicles from superoxide dismutase 1 (SOD1)G93A ALS mice originate from astrocytes and neurons and carry misfolded SOD1","volume":"294","author":"Silverman","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/ana.21147","article-title":"Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations","volume":"61","author":"Mackenzie","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Benson, B.C., Shaw, P.J., Azzouz, M., Highley, J.R., and Hautbergue, G.M. (2021). Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.783624"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9349","DOI":"10.1093\/nar\/12.24.9349","article-title":"Human Cu\/Zn superoxide dismutase gene: Molecular characterization of its two mRNA species","volume":"12","author":"Sherman","year":"1984","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.nbd.2013.08.005","article-title":"Posttranscriptional regulation of SOD1 gene expression under oxidative stress: Potential role of ELAV proteins in sporadic ALS","volume":"60","author":"Milani","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.bbagrm.2015.11.009","article-title":"Hydrogen peroxide-mediated induction of SOD1 gene transcription is independent from Nrf2 in a cellular model of neurodegeneration","volume":"1859","author":"Milani","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bordoni, M., Pansarasa, O., Dell\u2019Orco, M., Crippa, V., Gagliardi, S., Sproviero, D., Bernuzzi, S., Diamanti, L., Ceroni, M., and Tedeschi, G. (2019). Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8050729"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Meiering, E.M. (2008). The threat of instability: Neurodegeneration predicted by protein destabilization and aggregation propensity. PLoS Biol., 6.","DOI":"10.1371\/journal.pbio.0060193"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"McAlary, L., Plotkin, S.S., Yerbury, J.J., and Cashman, N.R. (2019). Prion-Like Propagation of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00262"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1089\/ars.2011.4328","article-title":"Amyotrophic lateral sclerosis: New insights into underlying molecular mechanisms and opportunities for therapeutic intervention","volume":"17","author":"Cozzolino","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Motataianu, A., Serban, G., Barcutean, L., and Balasa, R. (2022). Oxidative Stress in Amyotrophic Lateral Sclerosis: Synergy of Genetic and Environmental Factors. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169339"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pal, S., Tiwari, A., Sharma, K., and Sharma, S.K. (2020). Does conserved domain SOD1 mutation has any role in ALS severity and therapeutic outcome?. BMC Neurosci., 21.","DOI":"10.1186\/s12868-020-00591-3"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Berdy\u0144ski, M., Miszta, P., Safranow, K., Andersen, P.M., Morita, M., Filipek, S., \u017bekanowski, C., and Ku\u017ama-Kozakiewicz, M. (2022). SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity. Sci. Rep., 12.","DOI":"10.1038\/s41598-021-03891-8"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.neurol.2021.03.001","article-title":"Phenotypic variability in amyotrophic lateral sclerosis","volume":"177","author":"Couratier","year":"2021","journal-title":"Rev. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3109\/21678421.2015.1049183","article-title":"A revision of the El Escorial criteria\u20142015","volume":"16","author":"Ludolph","year":"2015","journal-title":"Amyotroph. Lateral Scler. Front. Degener"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Filosto, M., Piccinelli, S.C., Palmieri, I., Necchini, N., Valente, M., Zanella, I., Biasiotto, G., Di Lorenzo, D., Cereda, C., and Padovani, A. (2018). A Novel Mutation in the Stalk Domain of KIF5A Causes a Slowly Progressive Atypical Motor Syndrome. J. Clin. Med., 8.","DOI":"10.3390\/jcm8010017"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1080\/17434470410019906","article-title":"ALSFRS-R","volume":"5","author":"Gordon","year":"2004","journal-title":"Amyotroph. Lateral Scler. Other Mot. Neuron Disord."},{"key":"ref_36","first-page":"5021694","article-title":"Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention","volume":"2020","author":"Montezinho","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.2147\/JIR.S298307","article-title":"Complement Profiles in Patients with Amyotrophic Lateral Sclerosis: A Prospective Observational Cohort Study","volume":"14","author":"Pilely","year":"2021","journal-title":"J. Inflamm. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6788\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:10:13Z","timestamp":1760033413000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6788"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,15]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146788"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146788","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,7,15]]}}}