Astrocytes display cell autonomous and diverse early reactive states in familial amyotrophic lateral sclerosis

Author:

Taha Doaa M123,Clarke Benjamin E12,Hall Claire E12,Tyzack Giulia E12,Ziff Oliver J12,Greensmith Linda1,Kalmar Bernadett1ORCID,Ahmed Mhoriam1,Alam Aftab4ORCID,Thelin Eric P4ORCID,Garcia Nuria Marco4,Helmy Adel4,Sibley Christopher R5678,Patani Rickie12ORCID

Affiliation:

1. Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK

2. The Francis Crick Institute, London NW1 1AT, UK

3. Zoology Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt

4. Division of Neurosurgery and Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK

5. Institute of Quantitative Biology, Biochemistry and Biotechnology, School of Biological Sciences, University of Edinburgh, Edinburgh EH8 9JZ, UK

6. Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK

7. Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK

8. Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, EH16 4SB, UK

Abstract

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.

Funder

Cancer Research UK

UK Medical Research Council

Wellcome Trust

MRC Senior Clinical Fellowship

Wellcome Trust and the Royal Society

Wellcome Trust Seed Award

Swedish Society for Medical Research

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

Reference30 articles.

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5. Astrocyte-immune cell interactions in physiology and pathology;Han;Immunity,2021

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