Nitric oxide mediates glial-induced neurodegeneration in Alexander disease

Liqun Wang, Tracy L. Hagemann, Hermann Kalwa, Thomas Michel, Albee Messing and Mel B. Feany ()
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Liqun Wang: Brigham and Women’s Hospital, Harvard Medical School
Tracy L. Hagemann: Waisman Center, and School of Veterinary Medicine, University of Wisconsin-Madison
Hermann Kalwa: Brigham and Women’s Hospital, Harvard Medical School
Thomas Michel: Brigham and Women’s Hospital, Harvard Medical School
Albee Messing: Waisman Center, and School of Veterinary Medicine, University of Wisconsin-Madison
Mel B. Feany: Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Glia play critical roles in maintaining the structure and function of the nervous system; however, the specific contribution that astroglia make to neurodegeneration in human disease states remains largely undefined. Here we use Alexander disease, a serious degenerative neurological disorder caused by astrocyte dysfunction, to identify glial-derived NO as a signalling molecule triggering astrocyte-mediated neuronal degeneration. We further find that NO acts through cGMP signalling in neurons to promote cell death. Glial cells themselves also degenerate, via the DNA damage response and p53. Our findings thus define a specific mechanism for glial-induced non-cell autonomous neuronal cell death, and identify a potential therapeutic target for reducing cellular toxicity in Alexander disease, and possibly other neurodegenerative disorders with glial dysfunction.

Date: 2015
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DOI: 10.1038/ncomms9966

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