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dc.contributor.authorAdey, Brett N
dc.contributor.authorCooper-Knock, Johnathan
dc.contributor.authorKhleifat, Ahmad Al
dc.contributor.authorFogh, Isabella
dc.contributor.authorVan Damme, Philip
dc.contributor.authorCorcia, Philippe
dc.contributor.authorCouratier, Philippe
dc.contributor.authorHardiman, Orla
dc.contributor.authorMcLaughlin, Russell
dc.contributor.authorGotkine, Marc
dc.contributor.authorDrory, Vivian
dc.contributor.authorSilani, Vincenzo
dc.contributor.authorTicozzi, Nicola
dc.contributor.authorVeldink, Jan H.
dc.contributor.authorvan den Berg, Leonard H.
dc.contributor.authorde Carvalho, Mamede
dc.contributor.authorPinto, Susana
dc.contributor.authorMora Pardina, Jesus S.
dc.contributor.authorPovedano, Monica
dc.contributor.authorAndersen, Peter M.
dc.contributor.authorWeber, Markus
dc.contributor.authorBaşak, Nazli A.
dc.contributor.authorShaw, Christopher E
dc.contributor.authorShaw, Pamela J.
dc.contributor.authorMorrison, Karen E.
dc.contributor.authorLanders, John E
dc.contributor.authorGlass, Jonathan D.
dc.contributor.authorVourc’h, Patrick
dc.contributor.authorDobson, Richard JB
dc.contributor.authorBreen, Gerome
dc.contributor.authorAl-Chalabi, Ammar
dc.contributor.authorJones, Ashley R
dc.contributor.authorIacoangeli, Alfredo
dc.date.accessioned2023-02-01T16:03:17Z
dc.date.available2023-02-01T16:03:17Z
dc.date.issued2022-11-05
dc.identifier.citationLarge-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival Brett N Adey, Johnathan Cooper-Knock, Ahmad Al Khleifat, Isabella Fogh, Philip van Damme, Philippe Corcia, Philippe Couratier, Orla Hardiman, Russell McLaughlin, Marc Gotkine, Vivian Drory, Vincenzo Silani, Nicola Ticozzi, Jan H. Veldink, Leonard H. van den Berg, Mamede de Carvalho, Susana Pinto, Jesus S. Mora Pardina, Monica Povedano, Peter M. Andersen, Markus Weber, Nazli A. Başak, Christopher E Shaw, Pamela J. Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, Patrick Vourc’h, Richard JB Dobson, Gerome Breen, Ammar Al-Chalabi, Ashley R Jones, Alfredo Iacoangeli medRxiv 2022.11.04.22281798; doi: https://doi.org/10.1101/2022.11.04.22281798en_US
dc.identifier.doi10.1101/2022.11.04.22281798en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51627
dc.descriptionThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.en_US
dc.description.abstractCaveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in ALS. Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.en_US
dc.language.isoen_USen_US
dc.publisherCold Spring Harbor Laboratoryen_US
dc.relationNow published in Frontiers in Cellular Neuroscience doi: 10.3389/fncel.2023.1112405
dc.relation.ispartofmedRxiven_US
dc.relation.urlhttps://doi.org/10.1101/2022.11.04.22281798en_US
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectGenetic and Genomic Medicineen_US
dc.subjectamyotrophic lateral sclerosisen_US
dc.titleLarge-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival [preprint]en_US
dc.typePreprinten_US
dc.source.journaltitlemedRxiv
refterms.dateFOA2023-02-01T16:03:18Z
dc.contributor.departmentNeurologyen_US


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The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.