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Neurodegenerative disorders

Astrocytes turn nasty

Nature Reviews Drug Discovery volume 6, pages 434–435 (2007)Cite this article

ALS is a late-onset, progressive and fatal motor neuron disease. Previous work on familial ALS implicated both cell-autonomous and non-cell-autonomous effects of mutant SOD1 in motor neuron death, but the mechanism(s) of SOD1-induced toxicity was poorly understood. Eggan and colleagues set out to establish an in vitro model system to investigate this. They co-cultured embryonic stem cell (ESC)-derived motor neurons and glia from mice expressing mutant or wild-type Sod1. As expected, the survival of motor neurons expressing mutant Sod1 was lower than that of neurons differentiated from wild-type mice, indicating that mutant SOD1 increases the vulnerability of motor neurons to neurodegeneration. However, the survival of mutant motor neurons was further reduced when they were co-cultured with glia that also expressed mutant Sod1. Furthermore, mutant glia were able to dramatically reduce the survival of wild-type motor neurons, suggesting that a non-cell-autonomous effect of mutant SOD1 might contribute to the pathology of ALS.

These results were supported by a separate study in which Przedborski and colleagues examined the effects of astrocytes, the most abundant type of glia, expressing mutated Sod1, on primary and ESC-derived motor neurons. Conditioned media derived from the mutated astrocytes triggered motor neuron death through a BAX-dependent pathway, suggesting that as yet unidentified soluble factors secreted from these glial cells are sufficient to trigger apoptosis. The authors also showed that this finding is specific for motor neurons and astrocytes; astrocytes carrying SOD1 mutations did not damage other neuronal cell types, and motor neurons were immune to other mutant Sod1-expressing cell types.

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References

ORIGINAL RESEARCH PAPERS

  1. 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. Nature Neurosci. 10, 608–615 (2007)

    Article  CAS  Google Scholar 

  2. Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD release factors selectively toxic to motor neurons. Nature Neurosci. 10, 615–623 (2007)

    Article  CAS  Google Scholar 

FURTHER READING

  1. Pasinelli, P. & Brown, R. H. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nature Rev. Neurosci. 7, 710–723 (2006)

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Authors
  1. Monica Hoyos Flight
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Flight, M. Astrocytes turn nasty. Nat Rev Drug Discov 6, 434–435 (2007). https://doi.org/10.1038/nrd2343

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