Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity

Anastasya Birger, Israel Ben-Dor, Miri Ottolenghi, Tikva Turetsky, Yaniv Gil, Sahar Sweetat, Liat Perez, Vitali Belzer, Natania Casden, Debora Steiner, Michal Izrael, Eithan Galun, Eva Feldman, Oded Behar*, Benjamin Reubinoff

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons (MNs). It was shown that human astrocytes with mutations in genes associated with ALS, like C9orf72 (C9) or SOD1, reduce survival of MNs. Astrocyte toxicity may be related to their dysfunction or the release of neurotoxic factors. Methods: We used human induced pluripotent stem cell-derived astrocytes from ALS patients carrying C9orf72 mutations and non-affected donors. We utilized these cells to investigate astrocytic induced neuronal toxicity, changes in astrocyte transcription profile as well as changes in secretome profiles. Findings: We report that C9-mutated astrocytes are toxic to MNs via soluble factors. The toxic effects of astrocytes are positively correlated with the length of astrocyte propagation in culture, consistent with the age-related nature of ALS. We show that C9-mutated astrocytes downregulate the secretion of several antioxidant proteins. In line with these findings, we show increased astrocytic oxidative stress and senescence. Importantly, media conditioned by C9-astrocytes increased oxidative stress in wild type MNs. Interpretation: Our results suggest that dysfunction of C9-astrocytes leads to oxidative stress of themselves and MNs, which probably contributes to neurodegeneration. Our findings suggest that therapeutic strategies in familial ALS must not only target MNs but also focus on astrocytes to abrogate nervous system injury.

Original languageAmerican English
Pages (from-to)274-289
Number of pages16
JournaleBioMedicine
Volume50
DOIs
StatePublished - Dec 2019

Bibliographical note

Funding Information:
This work was kindly supported by a donation from the late Alfred Taubman (B.R. and E.L.F) and the Sinai Medical Staff Foundation (E.L.F), a donation from Judy and Sydney Swartz (B.R.) a grant from Legacy Heritage Biomedical Fund (Grant No. 1306/10, O.B. and B.R.), the Israel Science Foundation Grant No. 947/14 , and 401/19 O.B.) and by a research grant from Kadimastem Ltd (B.R.).

Publisher Copyright:
© 2019 The Authors

Keywords

  • Amyotrophic lateral sclerosis
  • Astrocytes
  • Neurotoxicity
  • Oxidative stress
  • Senescence
  • iPSC

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