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dc.contributor.authorBroadhead, Matthew J.
dc.contributor.authorBonthron, Calum
dc.contributor.authorWaddington, Julia
dc.contributor.authorSmith, William V.
dc.contributor.authorLopez, Maite F.
dc.contributor.authorBurley, Sarah
dc.contributor.authorValli, Jessica
dc.contributor.authorZhu, Fei
dc.contributor.authorKomiyama, Noboru H.
dc.contributor.authorSmith, Colin
dc.contributor.authorGrant, Seth G.N.
dc.contributor.authorMiles, Gareth B.
dc.date.accessioned2022-03-24T09:41:02Z
dc.date.available2022-03-24T09:41:02Z
dc.date.issued2022-04
dc.identifier.citationBroadhead , M J , Bonthron , C , Waddington , J , Smith , W V , Lopez , M F , Burley , S , Valli , J , Zhu , F , Komiyama , N H , Smith , C , Grant , S G N & Miles , G B 2022 , ' Selective vulnerability of tripartite synapses in Amyotrophic Lateral Sclerosis ' , Acta Neuropathologica , vol. 143 , no. 4 , pp. 471–486 . https://doi.org/10.1007/s00401-022-02412-9en
dc.identifier.issn0001-6322
dc.identifier.otherPURE: 278212479
dc.identifier.otherPURE UUID: 728ea93c-b880-4391-a4af-0c8072c72323
dc.identifier.otherScopus: 85126534248
dc.identifier.otherORCID: /0000-0002-8624-4625/work/110423178
dc.identifier.otherWOS: 000770724000001
dc.identifier.urihttp://hdl.handle.net/10023/25081
dc.descriptionAuthors would like to acknowledge the following funders: Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), the Euan MacDonald Centre and Chief Scientist Office, The European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (695568 SYNNOVATE), Simons Foundation Autism Research Initiative (529085), and the Wellcome Trust (Technology Development grant 202932).en
dc.description.abstractAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost, while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.
dc.language.isoeng
dc.relation.ispartofActa Neuropathologicaen
dc.rightsCopyright © The Author(s) 2022. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.en
dc.subjectALS/MNDen
dc.subjectSynapseen
dc.subjectAstrocyteen
dc.subjectNeurodegenerationen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.subjectNDASen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.subject.lccRC0321en
dc.titleSelective vulnerability of tripartite synapses in Amyotrophic Lateral Sclerosisen
dc.typeJournal articleen
dc.contributor.sponsorChief Scientist Officeen
dc.contributor.sponsorMotor Neurone Disease Associationen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Psychology and Neuroscienceen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Sir James Mackenzie Institute for Early Diagnosisen
dc.contributor.institutionUniversity of St Andrews. Centre for Biophotonicsen
dc.contributor.institutionUniversity of St Andrews. Institute of Behavioural and Neural Sciencesen
dc.identifier.doihttps://doi.org/10.1007/s00401-022-02412-9
dc.description.statusPeer revieweden
dc.identifier.grantnumber3752534en
dc.identifier.grantnumber137/813en


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