Astrocytes from familial and sporadic ALS patients are toxic to motor neurons (original) (raw)

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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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

Authors

  1. Amanda M Haidet-Phillips
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  2. Mark E Hester
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  3. Carlos J Miranda
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  4. Kathrin Meyer
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  5. Lyndsey Braun
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  6. Ashley Frakes
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  7. SungWon Song
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  8. Shibi Likhite
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  9. Matthew J Murtha
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  10. Kevin D Foust
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  11. Meghan Rao
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  12. Amy Eagle
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  13. Anja Kammesheidt
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  14. Ashley Christensen
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  15. Jerry R Mendell
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  16. Arthur H M Burghes
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  17. 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 toBrian K Kaspar.

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The authors declare no competing financial interests.

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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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