Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes

Glaucoma is characterized by a progressive loss of retinal ganglion cells and their axons, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (...

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Bibliographic Details
Published in:Cell death & disease 2018-02, Vol.9 (3), p.285-18, Article 285
Main Authors: Shim, Myoung Sup, Kim, Keun-Young, Bu, Jung Hyun, Nam, Hye Seung, Jeong, Seung Won, Park, Tae Lim, Ellisman, Mark H., Weinreb, Robert N., Ju, Won-Kyu
Format: Article
Language:English
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AKT protein
Antibodies
Astrocytes
Axons
Bax protein
Biochemistry
Biomedical and Life Sciences
Caspase
Caspase-3
Cell activation
Cell Biology
Cell Culture
Cell death
Cyclic AMP
Glaucoma
Immunology
Intracellular
Intracellular signalling
Kinases
Life Sciences
Neurodegeneration
Optic nerve
Oxidative stress
Phosphorylation
Protein expression
Protein kinase A
Retina
Retinal ganglion cells
Signal transduction
Structure-function relationships
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Summary:Glaucoma is characterized by a progressive loss of retinal ganglion cells and their axons, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role. However, whether the activation of cyclic adenosine 3′,5′-monophosphate (cAMP) signaling pathway is associated with astrocyte dysfunction in the ONH remains unknown. We report here that the cAMP/protein kinase A (PKA) pathway is critical to ONH astrocyte dysfunction, leading to caspase-3 activation and cell death via the AKT/Bim/Bax signaling pathway. Furthermore, elevated intracellular cAMP exacerbates vulnerability to oxidative stress in ONH astrocytes, and this may contribute to axonal damage in glaucomatous neurodegeneration. Inhibition of intracellular cAMP/PKA signaling activation protects ONH astrocytes by increasing AKT phosphorylation against oxidative stress. These results strongly indicate that activation of cAMP/PKA pathway has an important role in astrocyte dysfunction, and suggest that modulating cAMP/PKA pathway has therapeutic potential for glaucomatous ONH degeneration.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-017-0171-8