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  • Adey, Brett N.Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (author)

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023-03-02
  • Frontiers Media S.A.2023
  • electronicrdacarrier

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  • LIBRIS-ID:oai:DiVA.org:umu-206031
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-206031URI
  • https://doi.org/10.3389/fncel.2023.1112405DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Introduction: Caveolin-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 amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts.Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 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.Results: 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.Discussion: 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.

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  • Cooper-Knock, JohnathanSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom (author)
  • Al Khleifat, AhmadDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (author)
  • Fogh, IsabellaDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (author)
  • van Damme, PhilipDepartment of Neurosciences, KU Leuven-University of Leuven, Experimental Neurology, Leuven Brain Institute (LBI), Leuven, Belgium; VIB, Center for Brain and Disease Research, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium (author)
  • Corcia, PhilippeUMR 1253, Université de Tours, Inserm, Tours, France; Centre de référence sur la SLA, CHU de Tours, Tours, France (author)
  • Couratier, PhilippeCentre de référence sur la SLA, CHRU de Limoges, Limoges, France; UMR 1094, Université de Limoges, Inserm, Limoges, France (author)
  • Hardiman, OrlaAcademic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland (author)
  • McLaughlin, RussellComplex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland (author)
  • Gotkine, MarcFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah Medical Center, Jerusalem, Israel (author)
  • Drory, VivianDepartment of Neurology, Tel-Aviv Sourasky Medical Centre, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel (author)
  • Silani, VincenzoDepartment of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy (author)
  • Ticozzi, NicolaDepartment of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Pathophysiology and Transplantation, “Dino Ferrari” Center, Università degli Studi di Milano, Milan, Italy (author)
  • Veldink, Jan H.Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands (author)
  • van den Berg, Leonard H.Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands (author)
  • de Carvalho, MamedeInstituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal (author)
  • Pinto, SusanaUmeå universitet,Neurovetenskaper,Instituto de Fisiologia, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal (author)
  • Mora Pardina, Jesus S.ALS Unit, Hospital San Rafael, Madrid, Spain (author)
  • Povedano Panades, MónicaFunctional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Barcelona, L’Hospitalet de Llobregat, Spain (author)
  • Andersen, Peter M.,1962-Umeå universitet,Neurovetenskaper(Swepub:umu)pean0001 (author)
  • Weber, MarkusNeuromuscular Diseases Unit/ALS Clinic, St. Gallen, Switzerland (author)
  • Başak, Nazli A.Koc University School of Medicine, Translational Medicine Research Center, NDAL, Istanbul, Turkey (author)
  • Shaw, Christopher E.Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (author)
  • Shaw, Pamela J.Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom (author)
  • Morrison, Karen E.School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom (author)
  • Landers, John E.Department of Neurology, University of Massachusetts Medical School, MA, Worcester, United States (author)
  • Glass, Jonathan D.Department of Neurology, Emory University School of Medicine, GA, Atlanta, United States (author)
  • Vourc’h, PatrickDepartment of Neurology, University Hospitals Leuven, Leuven, Belgium; Service de Biochimie et Biologie molécularie, CHU de Tours, Tours, France (author)
  • Dobson, Richard J. B.Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London, Maudsley NHS Foundation Trust, King’s College London, London, United Kingdom; Institute of Health Informatics, University College London, London, United Kingdom; NIHR Biomedical Research Centre at University College London Hospitals, NHS Foundation Trust, London, United Kingdom (author)
  • Breen, GeromeSocial Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (author)
  • Al-Chalabi, AmmarDepartment of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; King’s College Hospital, London, United Kingdom (author)
  • Jones, Ashley R.Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom (author)
  • Iacoangeli, AlfredoDepartment of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London, Maudsley NHS Foundation Trust, King’s College London, London, United Kingdom (author)
  • Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom; Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United KingdomSheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom (creator_code:org_t)

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  • In:Frontiers in Cellular Neuroscience: Frontiers Media S.A.171662-5102

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