Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.
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Authors
Taha, Doaa M
Clarke, Benjamin E
Hall, Claire E
Tyzack, Giulia E
Ziff, Oliver J
Greensmith, Linda
Ahmed, Mhoriam
Garcia, Nuria Marco
Helmy, Adel
Sibley, Christopher R
Publication Date
2022-04-18Journal Title
Brain
ISSN
0006-8950
Publisher
Oxford University Press (OUP)
Type
Article
This Version
VoR
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Taha, D. M., Clarke, B. E., Hall, C. E., Tyzack, G. E., Ziff, O. J., Greensmith, L., Kalmar, B., et al. (2022). Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis.. Brain https://doi.org/10.1093/brain/awab328
Abstract
Amyotrophic 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.
Keywords
amyotrophic lateral sclerosis (ALS), astrocytes, cell autonomous, diversity, reactive transformation
Sponsorship
Royal College of Surgeons of England (2016/2017)
Identifiers
External DOI: https://doi.org/10.1093/brain/awab328
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332826
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