Nitric oxide mediates glial-induced neurodegeneration in Alexander disease.

Liqun Wang,Tracy L Hagemann,Hermann Kalwa,Albee Messing,Mel B Feany,Thomas Michel

doi:10.1038/ncomms9966

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.

Highlights

Glia play critical roles in maintaining the structure and function of the nervous system; the specific contribution that astroglia make to neurodegeneration in human disease states remains largely undefined
Given evidence from patients and mouse models[3,6,7] for a toxic dominant gain-of-function mechanism related to abnormal aggregation and toxicity of glial fibrillary acidic protein (GFAP) in Alexander disease, we have modelled the disorder by expressing disease-linked forms of human GFAP in fly glia[8]
To identify genetic modifiers of GFAP toxicity in an unbiased pattern, we performed an unbiased forward genetic screen using a collection of 2,239 transgenic RNA interference (RNAi) lines[14]

Summary

Introduction

Glia play critical roles in maintaining the structure and function of the nervous system; the specific contribution that astroglia make to neurodegeneration in human disease states remains largely undefined. It has been challenging to identify the molecular underpinnings of glial-induced neuronal death and test cell-type-specific mechanisms in vivo To address these limitations, we have developed a model of a glial-based neurodegenerative disorder, Alexander disease, in the genetically accessible model organism Drosophila. Alexander disease offers a unique opportunity to study glial-mediated neurodegeneration, because the primary abnormality in patients is glial: dominant missense mutations in the gene encoding glial fibrillary acidic protein (GFAP), the intermediate filament of astrocytes[3] Clinical presentations of this rare, but informative, disorder range from infants with prominent leukodystrophy and seizures to adults with relative preservation of myelin and a movement disorder[4,5]. Using a newly developed dual-expression system, we demonstrate a key role for NO synthesized and released in glia acting through neuronal NO targets to promote neuronal cell death

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Results

Conclusion