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Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral scleros...

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Autores principales: Szego, Eva M, Malz, Laura, Bernhardt, Nadine, Rösen-Wolff, Angela, Falkenburger, Björn H, Luksch, Hella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767458/
https://www.ncbi.nlm.nih.gov/pubmed/36314770
http://dx.doi.org/10.7554/eLife.81943
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author Szego, Eva M
Malz, Laura
Bernhardt, Nadine
Rösen-Wolff, Angela
Falkenburger, Björn H
Luksch, Hella
author_facet Szego, Eva M
Malz, Laura
Bernhardt, Nadine
Rösen-Wolff, Angela
Falkenburger, Björn H
Luksch, Hella
author_sort Szego, Eva M
collection PubMed
description Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral sclerosis, and the STING pathway has been implicated in the pathogenesis of further neurodegenerative diseases. To test whether STING activation is sufficient to induce neurodegeneration, we analysed a mouse model that expresses the constitutively active STING variant N153S. In this model, we focused on dopaminergic neurons, which are particularly sensitive to stress and represent a circumscribed population that can be precisely quantified. In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. These neuroinflammatory markers were already elevated in juvenile mice although at this age the number of dopaminergic neurons was still unaffected, thus preceding the degeneration of dopaminergic neurons. More neuroinflammatory markers were blunted in mice deficient for inflammasomes than in mice deficient for signalling by type I interferons. Neurodegeneration, however, was blunted in both mice. Collectively, these findings demonstrate that chronic activation of the STING pathway is sufficient to cause degeneration of dopaminergic neurons. Targeting the STING pathway could therefore be beneficial in Parkinson’s disease and further neurodegenerative diseases.
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spelling pubmed-97674582022-12-21 Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice Szego, Eva M Malz, Laura Bernhardt, Nadine Rösen-Wolff, Angela Falkenburger, Björn H Luksch, Hella eLife Neuroscience Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral sclerosis, and the STING pathway has been implicated in the pathogenesis of further neurodegenerative diseases. To test whether STING activation is sufficient to induce neurodegeneration, we analysed a mouse model that expresses the constitutively active STING variant N153S. In this model, we focused on dopaminergic neurons, which are particularly sensitive to stress and represent a circumscribed population that can be precisely quantified. In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. These neuroinflammatory markers were already elevated in juvenile mice although at this age the number of dopaminergic neurons was still unaffected, thus preceding the degeneration of dopaminergic neurons. More neuroinflammatory markers were blunted in mice deficient for inflammasomes than in mice deficient for signalling by type I interferons. Neurodegeneration, however, was blunted in both mice. Collectively, these findings demonstrate that chronic activation of the STING pathway is sufficient to cause degeneration of dopaminergic neurons. Targeting the STING pathway could therefore be beneficial in Parkinson’s disease and further neurodegenerative diseases. eLife Sciences Publications, Ltd 2022-10-31 /pmc/articles/PMC9767458/ /pubmed/36314770 http://dx.doi.org/10.7554/eLife.81943 Text en © 2022, Szego, Malz et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Szego, Eva M
Malz, Laura
Bernhardt, Nadine
Rösen-Wolff, Angela
Falkenburger, Björn H
Luksch, Hella
Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
title Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
title_full Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
title_fullStr Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
title_full_unstemmed Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
title_short Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
title_sort constitutively active sting causes neuroinflammation and degeneration of dopaminergic neurons in mice
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767458/
https://www.ncbi.nlm.nih.gov/pubmed/36314770
http://dx.doi.org/10.7554/eLife.81943
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