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dc.contributor.authorTaha, Doaa M
dc.contributor.authorClarke, Benjamin E
dc.contributor.authorHall, Claire E
dc.contributor.authorTyzack, Giulia E
dc.contributor.authorZiff, Oliver J
dc.contributor.authorGreensmith, Linda
dc.contributor.authorKalmar, Bernadett
dc.contributor.authorAhmed, Mhoriam
dc.contributor.authorAlam, Mohammed
dc.contributor.authorThelin, Eric
dc.contributor.authorGarcia, Nuria Marco
dc.contributor.authorHelmy, Adel
dc.contributor.authorSibley, Christopher R
dc.contributor.authorPatani, Rickie
dc.description.abstractAmyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations. We show that VCP mutant astrocytes undergo cell-autonomous reactive transformation characterized by increased expression of complement component 3 (C3) in addition to several characteristic gene expression changes. We then demonstrate that isochronic SOD1 mutant astrocytes also undergo a cell-autonomous reactive transformation, but that this is molecularly distinct from VCP mutant astrocytes. This is shown through transcriptome-wide analyses, identifying divergent gene expression profiles and activation of different key transcription factors in SOD1 and VCP mutant human induced pluripotent stem cell-derived astrocytes. Finally, we show functional differences in the basal cytokine secretome between VCP and SOD1 mutant human induced pluripotent stem cell-derived astrocytes. Our data therefore reveal that reactive transformation can occur cell autonomously in human amyotrophic lateral sclerosis astrocytes and with a striking degree of early molecular and functional heterogeneity when comparing different disease-causing mutations. These insights may be important when considering astrocyte reactivity as a putative therapeutic target in familial amyotrophic lateral sclerosis.
dc.publisherOxford University Press (OUP)
dc.rightsAttribution 4.0 International
dc.subjectamyotrophic lateral sclerosis (ALS)
dc.subjectcell autonomous
dc.subjectreactive transformation
dc.titleAstrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.
dc.publisher.departmentDepartment of Clinical Neurosciences
dc.contributor.orcidKalmar, Bernadett [0000-0003-3747-4843]
dc.contributor.orcidAlam, Mohammed [0000-0001-8089-6721]
dc.contributor.orcidThelin, Eric [0000-0002-2338-4364]
dc.contributor.orcidHelmy, Adel [0000-0002-0531-0556]
dc.contributor.orcidPatani, Rickie [0000-0002-3825-7675]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idRoyal College of Surgeons of England (2016/2017)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International