Large-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; Mónica Povedano Panades; 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 J.B. Dobson; Gerome Breen; Ammar Al-Chalabi; Ashley R. Jones; Alfredo Iacoangeli

doi:10.3389/fncel.2023.1112405

Large-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, Mónica Povedano Panades, Peter M. AndersenMarkus Weber, Nazli A. Başak, Christopher E. Shaw, Pamela J. Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, Patrick Vourc’h, Richard J.B. Dobson, Gerome Breen, Ammar Al-Chalabi, Ashley R. Jones, Alfredo Iacoangeli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

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.

Original language	English
Article number	1112405
Journal	Frontiers in cellular neuroscience
Volume	17
DOIs	https://doi.org/10.3389/fncel.2023.1112405
Publication status	Published - 2023

Keywords

ALS (Amyotrophic lateral sclerosis)
Cav
CAV1 and CAV2
caveolin
differential expression analysis (DEA)
enhancer variant
neurodegeneration
survival analysis

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10.3389/fncel.2023.1112405

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Adey, B. N., Cooper-Knock, J., Al Khleifat, A., Fogh, I., van Damme, P., Corcia, P., Couratier, P., Hardiman, O., McLaughlin, R., Gotkine, M., Drory, V., Silani, V., Ticozzi, N., Veldink, J. H., van den Berg, L. H., de Carvalho, M., Pinto, S., Mora Pardina, J. S., Povedano Panades, M., ... Iacoangeli, A. (2023). Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival. Frontiers in cellular neuroscience, 17, Article 1112405. https://doi.org/10.3389/fncel.2023.1112405

@article{a313ce7bf51449d6800eb3b14fbede40,

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

abstract = "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.",

keywords = "ALS (Amyotrophic lateral sclerosis), Cav, CAV1 and CAV2, caveolin, differential expression analysis (DEA), enhancer variant, neurodegeneration, survival analysis",

author = "Adey, {Brett N.} and Johnathan Cooper-Knock and {Al Khleifat}, Ahmad and Isabella Fogh and {van Damme}, Philip and Philippe Corcia and Philippe Couratier and Orla Hardiman and Russell McLaughlin and Marc Gotkine and Vivian Drory and Vincenzo Silani and Nicola Ticozzi and Veldink, {Jan H.} and {van den Berg}, {Leonard H.} and {de Carvalho}, Mamede and Susana Pinto and {Mora Pardina}, {Jesus S.} and {Povedano Panades}, M{\'o}nica and Andersen, {Peter M.} and Markus Weber and Ba{\c s}ak, {Nazli A.} and Shaw, {Christopher E.} and Shaw, {Pamela J.} and Morrison, {Karen E.} and Landers, {John E.} and Glass, {Jonathan D.} and Patrick Vourc{\textquoteright}h and Dobson, {Richard J.B.} and Gerome Breen and Ammar Al-Chalabi and Jones, {Ashley R.} and Alfredo Iacoangeli",

note = "Funding Information: We would like to acknowledge funding from the following funders: UK Research and Innovation; Medical Research Council; South London and Maudsley NHS Foundation Trust; MND Scotland; Motor Neurone Disease Association; National Institute for Health Research; Spastic Paraplegia Foundation; Rosetrees Trust; Darby Rimmer MND Foundation. Funding for open access charge: UKRI. BA acknowledges funding from an NIHR pre-doctoral fellowship (NIHR301067). AI is funded by the Motor Neurone Disease Association and South London and Maudsley NHS Foundation Trust. JC-K is supported by a Wellcome Trust fellowship (216596/Z/19/Z). AAK is funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609. DOI: 10.52546/pc.gr.150909.), The Motor Neurone Disease Association (MNDA) Fellowship (AAK/Oct21/975-799), The Darby Rimmer Foundation, and The NIHR Maudsley Biomedical Research Centre. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND: http://www.neurodegenerationresearch.eu/ [United Kingdom, Medical Research Council MR/L501529/1 to AA-C, principal investigator (PI) and MR/R024804/1 to AA-C, PI; Economic and Social Research Council ES/L008238/1 to AA-C (co-PI)] and through the Motor Neurone Disease Association. This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The work leading up to this publication was funded by the European Community{\textquoteright}s Horizon 2020 Programme (H2020-PHC-2014-two-stage; grant 633413). We acknowledge use of the research computing facility at King{\textquoteright}s College London, Rosalind ( https://rosalind.kcl.ac.uk ), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London and Maudsley and Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trusts and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy{\textquoteright}s and St Thomas{\textquoteright} Charity (TR130505). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King{\textquoteright}s College London, or the Department of Health and Social Care. Publisher Copyright: Copyright {\textcopyright} 2023 Adey, Cooper-Knock, Al Khleifat, Fogh, van Damme, Corcia, Couratier, Hardiman, McLaughlin, Gotkine, Drory, Silani, Ticozzi, Veldink, van den Berg, de Carvalho, Pinto, Mora Pardina, Povedano Panades, Andersen, Weber, Ba{\c s}ak, Shaw, Shaw, Morrison, Landers, Glass, Vourc{\textquoteright}h, Dobson, Breen, Al-Chalabi, Jones and Iacoangeli.",

year = "2023",

doi = "10.3389/fncel.2023.1112405",

language = "English",

volume = "17",

journal = "Frontiers in cellular neuroscience",

issn = "1662-5102",

publisher = "Frontiers Media S.A.",

}

Adey, BN, Cooper-Knock, J, Al Khleifat, A, Fogh, I, van Damme, P, Corcia, P, Couratier, P, Hardiman, O, McLaughlin, R, Gotkine, M, Drory, V, Silani, V, Ticozzi, N, Veldink, JH, van den Berg, LH, de Carvalho, M, Pinto, S, Mora Pardina, JS, Povedano Panades, M, Andersen, PM, Weber, M, Başak, NA, Shaw, CE, Shaw, PJ, Morrison, KE, Landers, JE, Glass, JD, Vourc’h, P, Dobson, RJB, Breen, G , Al-Chalabi, A, Jones, AR & Iacoangeli, A 2023, 'Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival', Frontiers in cellular neuroscience, vol. 17, 1112405. https://doi.org/10.3389/fncel.2023.1112405

TY - JOUR

T1 - Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

AU - Adey, Brett N.

AU - Cooper-Knock, Johnathan

AU - Al Khleifat, Ahmad

AU - Fogh, Isabella

AU - van Damme, Philip

AU - Corcia, Philippe

AU - Couratier, Philippe

AU - Hardiman, Orla

AU - McLaughlin, Russell

AU - Gotkine, Marc

AU - Drory, Vivian

AU - Silani, Vincenzo

AU - Ticozzi, Nicola

AU - Veldink, Jan H.

AU - van den Berg, Leonard H.

AU - de Carvalho, Mamede

AU - Pinto, Susana

AU - Mora Pardina, Jesus S.

AU - Povedano Panades, Mónica

AU - Andersen, Peter M.

AU - Weber, Markus

AU - Başak, Nazli A.

AU - Shaw, Christopher E.

AU - Shaw, Pamela J.

AU - Morrison, Karen E.

AU - Landers, John E.

AU - Glass, Jonathan D.

AU - Vourc’h, Patrick

AU - Dobson, Richard J.B.

AU - Breen, Gerome

AU - Al-Chalabi, Ammar

AU - Jones, Ashley R.

AU - Iacoangeli, Alfredo

N1 - Funding Information: We would like to acknowledge funding from the following funders: UK Research and Innovation; Medical Research Council; South London and Maudsley NHS Foundation Trust; MND Scotland; Motor Neurone Disease Association; National Institute for Health Research; Spastic Paraplegia Foundation; Rosetrees Trust; Darby Rimmer MND Foundation. Funding for open access charge: UKRI. BA acknowledges funding from an NIHR pre-doctoral fellowship (NIHR301067). AI is funded by the Motor Neurone Disease Association and South London and Maudsley NHS Foundation Trust. JC-K is supported by a Wellcome Trust fellowship (216596/Z/19/Z). AAK is funded by ALS Association Milton Safenowitz Research Fellowship (grant number 22-PDF-609. DOI: 10.52546/pc.gr.150909.), The Motor Neurone Disease Association (MNDA) Fellowship (AAK/Oct21/975-799), The Darby Rimmer Foundation, and The NIHR Maudsley Biomedical Research Centre. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND: http://www.neurodegenerationresearch.eu/ [United Kingdom, Medical Research Council MR/L501529/1 to AA-C, principal investigator (PI) and MR/R024804/1 to AA-C, PI; Economic and Social Research Council ES/L008238/1 to AA-C (co-PI)] and through the Motor Neurone Disease Association. This study represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The work leading up to this publication was funded by the European Community’s Horizon 2020 Programme (H2020-PHC-2014-two-stage; grant 633413). We acknowledge use of the research computing facility at King’s College London, Rosalind ( https://rosalind.kcl.ac.uk ), which is delivered in partnership with the National Institute for Health Research (NIHR) Biomedical Research Centres at South London and Maudsley and Guy’s and St. Thomas’ NHS Foundation Trusts and part-funded by capital equipment grants from the Maudsley Charity (award 980) and Guy’s and St Thomas’ Charity (TR130505). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, King’s College London, or the Department of Health and Social Care. Publisher Copyright: Copyright © 2023 Adey, Cooper-Knock, Al Khleifat, Fogh, van Damme, Corcia, Couratier, Hardiman, McLaughlin, Gotkine, Drory, Silani, Ticozzi, Veldink, van den Berg, de Carvalho, Pinto, Mora Pardina, Povedano Panades, Andersen, Weber, Başak, Shaw, Shaw, Morrison, Landers, Glass, Vourc’h, Dobson, Breen, Al-Chalabi, Jones and Iacoangeli.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - ALS (Amyotrophic lateral sclerosis)

KW - Cav

KW - CAV1 and CAV2

KW - caveolin

KW - differential expression analysis (DEA)

KW - enhancer variant

KW - neurodegeneration

KW - survival analysis

UR - http://www.scopus.com/inward/record.url?scp=85150359744&partnerID=8YFLogxK

U2 - 10.3389/fncel.2023.1112405

DO - 10.3389/fncel.2023.1112405

M3 - Article

AN - SCOPUS:85150359744

SN - 1662-5102

VL - 17

JO - Frontiers in cellular neuroscience

JF - Frontiers in cellular neuroscience

M1 - 1112405

ER -

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

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