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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References
Di Giorgio, F.P., Boulting, G.L., Bobrowicz, S. & Eggan, K.C. Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3, 637–648 (2008).
Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251–253 (2008).
Marchetto, M.C. et al. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3, 649–657 (2008).
Di Giorgio, F.P., Carrasco, M.A., Siao, M.C., Maniatis, T. & Eggan, K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat. Neurosci. 10, 608–614 (2007).
Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat. Neurosci. 10, 615–622 (2007).
Brown, R.H. Jr. Amyotrophic lateral sclerosis. Insights from genetics. Arch. Neurol. 54, 1246–1250 (1997).
Ilieva, H., Polymenidou, M. & Cleveland, D.W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).
Boillee, S., Vande Velde, C. & Cleveland, D.W. ALS: a disease of motor neurons and their non-neuronal neighbors. Neuron 52, 39–59 (2006).
Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).
Clement, A.M. et al. Wild-type non-neuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003).
Beers, D.R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103, 16021–16026 (2006).
Boulting, G.L. et al. A functionally characterized test set of human induced pluripotent stem cells. Nat. Biotechnol. 29, 279–286 (2011).
Dimos, J.T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008).
Glass, C.K., Saijo, K., Winner, B., Marchetto, M.C. & Gage, F.H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).
Dodge, J.C. et al. Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol. Ther. 16, 1056–1064 (2008).
Palmer, T.D. et al. Cell culture. Progenitor cells from human brain after death. Nature 411, 42–43 (2001).
Ray, J. & Gage, F.H. Differential properties of adult rat and mouse brain-derived neural stem/progenitor cells. Mol. Cell. Neurosci. 31, 560–573 (2006).
Cahoy, J.D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008).
Wichterle, H., Lieberam, I., Porter, J.A. & Jessell, T.M. Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385–397 (2002).
Dodge, J.C. et al. AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice. Mol. Ther. 18, 2075–2084 (2010).
Lobsiger, C.S., Boillee, S. & Cleveland, D.W. Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc. Natl. Acad. Sci. USA 104, 7319–7326 (2007).
Wang, R., Yang, B. & Zhang, D. Activation of interferon signaling pathways in spinal cord astrocytes from an ALS mouse model. Glia 59, 946–958 (2011).
Bendotti, C. et al. Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase. Neurodegener. Dis. 2, 128–134 (2005).
Miller, T.M. et al. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Ann. Neurol. 57, 773–776 (2005).
Bosco, D.A. et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat. Neurosci. 13, 1396–1403 (2010).
Gruzman, A. et al. Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 104, 12524–12529 (2007).
Zetterstrom, P., Graffmo, K.S., Andersen, P.M., Brannstrom, T. & Marklund, S.L. Proteins that bind to misfolded mutant superoxide dismutase-1 in spinal cords from transgenic ALS model mice. J. Biol. Chem. 286, 20130–20136 (2011).
Foust, K.D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59–65 (2009).
Lepore, A.C. et al. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat. Neurosci. 11, 1294–1301 (2008).
Hester, M.E. et al. Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol. Ther. (in the press).
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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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.
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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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DOI: https://doi.org/10.1038/nbt.1957