{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:16:32Z","timestamp":1790885792637,"version":"4.1.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS116143"],"award-info":[{"award-number":["R01NS116143"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103430"],"award-info":[{"award-number":["P20GM103430"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"RI-INBRE","award":["Early Career Development Award"],"award-info":[{"award-number":["Early Career Development Award"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1\/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the <jats:italic>C9ORF72<\/jats:italic> gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex specimens. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.<\/jats:p>","DOI":"10.1186\/s40478-024-01778-z","type":"journal-article","created":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T17:03:11Z","timestamp":1714064591000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["LINC complex alterations are a key feature of sporadic and familial ALS\/FTD"],"prefix":"10.1186","volume":"12","author":[{"given":"Riccardo","family":"Sirtori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"J. Gregoire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"M. Potts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liviana","family":"Donatelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8329-3467","authenticated-orcid":false,"given":"Claudia","family":"Fallini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,25]]},"reference":[{"key":"1778_CR1","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/S1474-4422(21)00465-8","volume":"21","author":"SA Goutman","year":"2022","unstructured":"Goutman SA et al (2022) Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol 21:480\u2013493","journal-title":"Lancet Neurol"},{"key":"1778_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011","author":"M DeJesus-Hernandez","year":"2011","unstructured":"DeJesus-Hernandez M et al (2011) Expanded GGGGCC hexanucleotide repeat in Noncoding Region of C9ORF72 causes chromosome 9p-Linked FTD and ALS. Neuron. https:\/\/doi.org\/10.1016\/j.neuron.2011.09.011","journal-title":"Neuron"},{"key":"1778_CR3","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1212\/WNL.0000000000003067","volume":"87","author":"ME Umoh","year":"2016","unstructured":"Umoh ME et al (2016) Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population. Neurology 87:1024\u20131030","journal-title":"Neurology"},{"key":"1778_CR4","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","volume":"351","author":"T Arai","year":"2006","unstructured":"Arai T et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602\u2013611","journal-title":"Biochem Biophys Res Commun"},{"key":"1778_CR5","unstructured":"J.C., G. et al. The nuclear pore complex is compromised in ALS. Amyotroph Lateral Scler Front Degener (2016)"},{"key":"1778_CR6","doi-asserted-by":"crossref","unstructured":"Riccardo Sirtori M, Gregoire A, Collins S, Santangelo B, Chatragadda R, Cullen (2024) Antonia Ratti, C. F. altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS\/FTD. 1","DOI":"10.1101\/2024.02.01.578318"},{"key":"1778_CR7","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.184184","author":"Z Jahed","year":"2016","unstructured":"Jahed Z, Soheilypour M, Peyro M, Mofrad MR (2016) K. The LINC and NPC relationship - it\u2019s complicated! J Cell Sci. https:\/\/doi.org\/10.1242\/jcs.184184","journal-title":"J Cell Sci"},{"key":"1778_CR8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.071910","author":"F Haque","year":"2010","unstructured":"Haque F et al (2010) Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes. J Biol Chem. https:\/\/doi.org\/10.1074\/jbc.M109.071910","journal-title":"J Biol Chem"},{"key":"1778_CR9","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky288","author":"R Pradhan","year":"2018","unstructured":"Pradhan R, Ranade D, Sengupta K (2018) Emerin modulates spatial organization of chromosome territories in cells on softer matrices. Nucleic Acids Res. https:\/\/doi.org\/10.1093\/nar\/gky288","journal-title":"Nucleic Acids Res"},{"key":"1778_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/srep38063","author":"SG Alam","year":"2016","unstructured":"Alam SG et al (2016) The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity. Sci Rep. https:\/\/doi.org\/10.1038\/srep38063","journal-title":"Sci Rep"},{"key":"1778_CR11","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2016.1149664","author":"A Matsumoto","year":"2016","unstructured":"Matsumoto A et al (2016) Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli. Nucleus. https:\/\/doi.org\/10.1080\/19491034.2016.1149664","journal-title":"Nucleus"},{"key":"1778_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13023-017-0698-x","volume":"12","author":"A Janin","year":"2017","unstructured":"Janin A, Bauer D, Ratti F, Millat G, M\u00e9jat A (2017) Nuclear envelopathies: a complex LINC between nuclear envelope and pathology. Orphanet J Rare Dis 12:1\u201316","journal-title":"Orphanet J Rare Dis"},{"key":"1778_CR13","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.ejcb.2012.03.003","volume":"91","author":"S Taranum","year":"2012","unstructured":"Taranum S et al (2012) LINC complex alterations in DMD and EDMD\/CMT fibroblasts. Eur J Cell Biol 91:614\u2013628","journal-title":"Eur J Cell Biol"},{"key":"1778_CR14","doi-asserted-by":"publisher","first-page":"3462","DOI":"10.1093\/hmg\/ddp290","volume":"18","author":"R Attali","year":"2009","unstructured":"Attali R et al (2009) Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis. Hum Mol Genet 18:3462\u20133469","journal-title":"Hum Mol Genet"},{"key":"1778_CR15","doi-asserted-by":"crossref","unstructured":"Young N et al (2021) Biallelic SYNE2 missense mutations leading to Nesprin-2 giant hypo-expression are associated with intellectual disability and autism. Genes (Basel). 12","DOI":"10.3390\/genes12091294"},{"key":"1778_CR16","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1093\/brain\/aww079","volume":"139","author":"M Synofzik","year":"2016","unstructured":"Synofzik M et al (2016) SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain 139:1378\u20131393","journal-title":"Brain"},{"key":"1778_CR17","doi-asserted-by":"crossref","unstructured":"Storey EC, Fuller HR (2022) Genotype-Phenotype Correlations in Human Diseases Caused by Mutations of LINC Complex-Associated Genes: A Systematic Review and Meta-Summary. Cells 11","DOI":"10.3390\/cells11244065"},{"key":"1778_CR18","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1080\/21678421.2020.1813312","volume":"22","author":"HNH Ishiura","year":"2021","unstructured":"Ishiura HNH, Y. T. T. JM M. T. T., Tsuji S (2021) Juvenile amyotrophic lateral sclerosis with complex phenotypes associated with novel SYNE1 mutations. Amyotroph Lateral Scler Front Degener 22:576\u2013578","journal-title":"Amyotroph Lateral Scler Front Degener"},{"key":"1778_CR19","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad291","author":"V Baskerville","year":"2023","unstructured":"Baskerville V, Rapuri S, Mehlhop E, Coyne AN (2023) SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis. Brain. https:\/\/doi.org\/10.1093\/brain\/awad291","journal-title":"Brain"},{"key":"1778_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-08724-w","author":"S Ryan","year":"2022","unstructured":"Ryan S, Rollinson S, Hobbs E, Pickering-Brown S (2022) C9orf72 dipeptides disrupt the nucleocytoplasmic transport machinery and cause TDP-43 mislocalisation to the cytoplasm. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-022-08724-w","journal-title":"Sci Rep"},{"key":"1778_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s42004-021-00547-6","author":"HM Chien","year":"2021","unstructured":"Chien HM et al (2021) Nanoscopic investigation of C9orf72 poly-GA oligomers on nuclear membrane disruption by a photoinducible platform. Commun Chem. https:\/\/doi.org\/10.1038\/s42004-021-00547-6","journal-title":"Commun Chem"},{"key":"1778_CR22","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nature14973","volume":"525","author":"K Zhang","year":"2015","unstructured":"Zhang K et al (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56\u201361","journal-title":"Nature"},{"key":"1778_CR23","unstructured":"C., D. et al. Nuclear pore abnormalities in C9orf72 ALS ips neurons and tissue alter nucleocytoplasmic protein trafficking. Amyotroph Lateral Scler Front Degener (2015)"},{"key":"1778_CR24","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1251-9","author":"J Cooper-Knock","year":"2014","unstructured":"Cooper-Knock J, Shaw PJ, Kirby J (2014) The widening spectrum of C9ORF72-related disease; Genotype\/phenotype correlations and potential modifiers of clinical phenotype. Acta Neuropathol. https:\/\/doi.org\/10.1007\/s00401-014-1251-9","journal-title":"Acta Neuropathol"},{"key":"1778_CR25","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.51","author":"MS Fernandopulle","year":"2018","unstructured":"Fernandopulle MS et al (2018) Transcription factor\u2013mediated differentiation of human iPSCs into neurons. Curr Protoc Cell Biol. https:\/\/doi.org\/10.1002\/cpcb.51","journal-title":"Curr Protoc Cell Biol"},{"key":"1778_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-1081-0","author":"JH Hor","year":"2018","unstructured":"Hor JH et al (2018) Cell cycle inhibitors protect motor neurons in an organoid model of spinal muscular atrophy. Cell Death Dis. https:\/\/doi.org\/10.1038\/s41419-018-1081-0","journal-title":"Cell Death Dis"},{"key":"1778_CR27","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.02471","author":"VC Padmakumar","year":"2005","unstructured":"Padmakumar VC et al (2005) The inner nuclear membrane protein Sun1 mediates the anchorage of Nesprin-2 to the nuclear envelope. J Cell Sci. https:\/\/doi.org\/10.1242\/jcs.02471","journal-title":"J Cell Sci"},{"key":"1778_CR28","unstructured":"Uptodate (2015) Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease. Physiol Res"},{"key":"1778_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2021.108829","author":"AA Khilan","year":"2021","unstructured":"Khilan AA, Al-Maslamani NA, Horn HF (2021) Cell stretchers and the LINC complex in mechanotransduction. Arch Biochem Biophys. https:\/\/doi.org\/10.1016\/j.abb.2021.108829","journal-title":"Arch Biochem Biophys"},{"key":"1778_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-017-0047-3","author":"CC Chou","year":"2018","unstructured":"Chou CC et al (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS\/FTD. Nat Neurosci. https:\/\/doi.org\/10.1038\/s41593-017-0047-3","journal-title":"Nat Neurosci"},{"key":"1778_CR31","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1038\/s41593-021-00859-9","volume":"24","author":"YC Lin","year":"2021","unstructured":"Lin YC et al (2021) Interactions between ALS-linked FUS and nucleoporins are associated with defects in the nucleocytoplasmic transport pathway. Nat Neurosci 24:1077\u20131088","journal-title":"Nat Neurosci"},{"key":"1778_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11837-y","author":"A Giampetruzzi","year":"2019","unstructured":"Giampetruzzi A et al (2019) Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis. Nat Commun. https:\/\/doi.org\/10.1038\/s41467-019-11837-y","journal-title":"Nat Commun"},{"key":"1778_CR33","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E19-01-0027","author":"LM Hoffman","year":"2020","unstructured":"Hoffman LM et al (2020) Mechanical stress triggers nuclear remodeling and the formation of transmembrane actin nuclear lines with associated nuclear pore complexes. Mol Biol Cell. https:\/\/doi.org\/10.1091\/mbc.E19-01-0027","journal-title":"Mol Biol Cell"},{"key":"1778_CR34","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1007\/s00294-019-00999-3","volume":"65","author":"H Cantwell","year":"2019","unstructured":"Cantwell H, Nurse P (2019) Unravelling nuclear size control. Curr Genet 65:1281\u20131285","journal-title":"Curr Genet"},{"key":"1778_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40478-021-01125-6","volume":"9","author":"O Aladesuyi Arogundade","year":"2021","unstructured":"Aladesuyi Arogundade O et al (2021) Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization. Acta Neuropathol Commun 9:1\u201316","journal-title":"Acta Neuropathol Commun"},{"key":"1778_CR36","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nature13124","volume":"507","author":"AR Haeusler","year":"2014","unstructured":"Haeusler AR et al (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507:195\u2013200","journal-title":"Nature"},{"key":"1778_CR37","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-021-00728-4","author":"N Sun","year":"2021","unstructured":"Sun N et al (2021) Applications of brain organoids in neurodevelopment and neurological diseases. J Biomed Sci. https:\/\/doi.org\/10.1186\/s12929-021-00728-4","journal-title":"J Biomed Sci"},{"key":"1778_CR38","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s00401-018-1934-8","volume":"137","author":"M Gautam","year":"2019","unstructured":"Gautam M et al (2019) Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology. Acta Neuropathol 137:47\u201369","journal-title":"Acta Neuropathol"},{"key":"1778_CR39","doi-asserted-by":"crossref","unstructured":"Du ZW et al (2015) Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat Commun 6","DOI":"10.1038\/ncomms7626"},{"key":"1778_CR40","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin J et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676\u2013682","journal-title":"Nat Methods"},{"key":"1778_CR41","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1921-0","author":"SC Vatsavayai","year":"2019","unstructured":"Vatsavayai SC, Nana AL, Yokoyama JS, Seeley WW (2019) C9orf72-FTD\/ALS pathogenesis: evidence from human neuropathological studies. Acta Neuropathol. https:\/\/doi.org\/10.1007\/s00401-018-1921-0","journal-title":"Acta Neuropathol"},{"key":"1778_CR42","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1793-8","author":"S Saberi","year":"2018","unstructured":"Saberi S et al (2018) Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis. Acta Neuropathol. https:\/\/doi.org\/10.1007\/s00401-017-1793-8","journal-title":"Acta Neuropathol"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-024-01778-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-024-01778-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-024-01778-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T17:06:46Z","timestamp":1714064806000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-024-01778-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,25]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["1778"],"URL":"https:\/\/doi.org\/10.1186\/s40478-024-01778-z","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,25]]},"assertion":[{"value":"8 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2024","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 authors have read and approved the manuscript for publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors have no relevant financial or non-financial interests to disclose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"69"}}