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Astrocytes from familial and sporadic ALS patients are toxic to motor neurons

Nature Biotechnology volume 29, pages 824–828 (2011)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, with astrocytes implicated as contributing substantially to motor neuron death in familial (F)ALS1,2,3,4,5. However, the proposed role of astrocytes in the pathology of ALS derives in part from rodent models of FALS based upon dominant mutations within the superoxide dismutase 1 (SOD1) gene, which account for <2% of all ALS cases2,4,5. Their role in sporadic (S)ALS, which affects >90% of ALS patients, remains to be established. Using astrocytes generated from postmortem tissue from both FALS and SALS patients, we show that astrocytes derived from both patient groups are similarly toxic to motor neurons. We also demonstrate that SOD1 is a viable target for SALS, as its knockdown significantly attenuates astrocyte-mediated toxicity toward motor neurons. Our data highlight astrocytes as a non–cell autonomous component in SALS and provide an in vitro model system to investigate common disease mechanisms and evaluate potential therapies for SALS and FALS.

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Figure 1: NPCs can be differentiated into highly enriched astrocyte cultures that show a similar gene profile to spinal cord primary astrocytes.
Figure 2: Astrocytes derived from SALS and FALS patients cause motor neuron death in coculture.
Figure 3: Activation of inflammatory genes in FALS and SALS astrocytes.
Figure 4: Suppression of SOD1 in both FALS and SALS astrocytes is motor neuron protective.

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Acknowledgements

This work was funded by US National Institutes of Health (NIH) R01 NS644912-1A1, RC2 NS69476-01, Project A.L.S. and Packard Center for ALS Research (P2ALS) and Helping Link Foundation to B.K.K., and an NIH grant NRSAF31NS058224 to A.M.H.-P., K.M. is supported by a fellowship from the Swiss National Science Foundation.

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Author notes

  1. Amanda M Haidet-Phillips, Mark E Hester and Carlos J Miranda: These authors contributed equally to this work.

Authors and Affiliations

  1. The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA

    Amanda M Haidet-Phillips, Mark E Hester, Carlos J Miranda, Kathrin Meyer, Lyndsey Braun, Ashley Frakes, SungWon Song, Shibi Likhite, Matthew J Murtha, Kevin D Foust, Meghan Rao, Amy Eagle, Jerry R Mendell & Brian K Kaspar

  2. Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, USA

    Amanda M Haidet-Phillips, Ashley Frakes, Jerry R Mendell & Brian K Kaspar

  3. Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA

    SungWon Song, Shibi Likhite, Matthew J Murtha & Brian K Kaspar

  4. Ambry Genetics, Aliso Viejo, California, USA

    Anja Kammesheidt & Ashley Christensen

  5. Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, USA

    Arthur H M Burghes

  6. Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA

    Brian K Kaspar

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Contributions

Conceived and designed the experiments: M.E.H., A.M.H.-P., C.J.M., A.H.M.B., J.R.M. and B.K.K. Performed the experiments: M.E.H., A.M.H.-P., C.J.M., K.M., L.B., A.F., S.S., S.L., M.J.M., K.D.F., M.R., A.E., A.K. and A.C. Analyzed the data: B.K.K., M.E.H., A.M.H. and C.J.M. Wrote the manuscript: M.E.H., A.M.H.-P., C.J.M. and B.K.K with input from the other co-authors.

Corresponding author

Correspondence to Brian K Kaspar.

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The authors declare no competing financial interests.

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Supplementary Tables 1–6 and Supplementary Figures 1–11 (PDF 5340 kb)

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Haidet-Phillips, A., Hester, M., Miranda, C. et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29, 824–828 (2011). https://doi.org/10.1038/nbt.1957

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