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Pathways leading to primary axonal injury in the motor axonal variant are well established, whereas mechanisms of secondary axonal injury in acute inflammatory demyelinating polyneuropathy (AIDP) are unknown. We recently developed an autoantibody\u2010and complement\u2010mediated model of murine AIDP, in which prominent injury to glial membranes at the node of Ranvier results in severe disruption to paranodal components. Acutely, axonal integrity was maintained, but over time secondary axonal degeneration occurred. Herein, we describe the differential mechanisms underlying acute glial membrane injury and secondary axonal injury in this model. Ex vivo nerve\u2010muscle explants were injured for either acute or extended periods with an autoantibody\u2010and complement\u2010mediated injury to glial paranodal membranes. This model was used to test several possible mechanisms of axon degeneration including calpain activation, and to monitor live axonal calcium signalling. Glial calpains induced acute disruption of paranodal membrane proteins in the absence of discernible axonal injury. Over time, we observed progressive axonal degeneration which was markedly attenuated by axon\u2010specific calpain inhibition. Injury was unaffected by all other tested methods of protection. Trans\u2010axolemmal diffusion of fluorescent proteins\u00a0 and live calcium imaging studies indirectly demonstrated the presence of nanoruptures in the axon membrane. This study outlines one mechanism by which secondary axonal degeneration arises in the AIDP variant of GBS where acute paranodal loop injury is prominent. The data also support the development of calpain inhibitors to attenuate both primary and secondary axonal degeneration in GBS.<\/jats:p>","DOI":"10.1111\/jns.12532","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T06:39:57Z","timestamp":1675060797000},"page":"17-31","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Axolemmal nanoruptures arising from paranodal membrane injury induce secondary axon degeneration in murine <scp>Guillain\u2010Barr\u00e9<\/scp> syndrome"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-6868","authenticated-orcid":false,"given":"Madeleine E.","family":"Cunningham","sequence":"first","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9571-2526","authenticated-orcid":false,"given":"Rhona","family":"McGonigal","sequence":"additional","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0378-6865","authenticated-orcid":false,"given":"Jennifer A.","family":"Barrie","sequence":"additional","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5778-3398","authenticated-orcid":false,"given":"Clare I.","family":"Campbell","sequence":"additional","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3031-126X","authenticated-orcid":false,"given":"Denggao","family":"Yao","sequence":"additional","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5997-1683","authenticated-orcid":false,"given":"Hugh J.","family":"Willison","sequence":"additional","affiliation":[{"name":"School of Infection &amp; Immunity University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000284"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082337"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012088592-3\/50081-5"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn281"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI158524"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4401-06.2007"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2004.051136"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.48.3.695"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/09638280701240326"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-8994(02)00626-4"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410390512"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67665-9"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(72)90001-9"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.55.4.552"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2020.135595"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq119"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awg254"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2022.114127"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/jns.12520","article-title":"The endogenous calpain inhibitor calpastatin attenuates axon degeneration in murine Guillain\u2010Barre syndrome","volume":"28","author":"McGonigal R","year":"2023","journal-title":"J Peripher Nerv Syst"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.9.5008-5018.2002"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2018.07.004"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwl074"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00315684"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.4103\/neuroindia.NI_1226_15"},{"issue":"11","key":"e_1_2_8_26_1","first-page":"2265","article-title":"Calpain inhibitor AK295 protects neurons from focal brain ischemia. 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