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

Abstract

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Eva M Szego

    Department of Neurology, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2629-2131
  2. Laura Malz

    Department of Pediatrics, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Nadine Bernhardt

    Department of Psychiatry, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3188-8431
  4. Angela Rösen-Wolff

    Department of Pediatrics, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Björn H Falkenburger

    Department of Neurology, TU Dresden, Dresden, Germany
    For correspondence
    Bjoern.Falkenburger@dzne.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2387-526X
  6. Hella Luksch

    Department of Pediatrics, TU Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.

Funding

Deutsche Forschungsgemeinschaft (FA-658-3-1)

  • Björn H Falkenburger

Deutsche Forschungsgemeinschaft (SFB TRR237,B18)

  • Björn H Falkenburger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Keqiang Ye, Chinese Academy of Sciences, China

Ethics

Animal experimentation: All animal experiments were carried out in accordance with the European CommunitiesCouncil Directive of November 24, 1986 (86/609/EEC) and approved by the LandesdirektionDresden, Germany.

Version history

  1. Preprint posted: February 4, 2022 (view preprint)
  2. Received: August 2, 2022
  3. Accepted: October 31, 2022
  4. Accepted Manuscript published: October 31, 2022 (version 1)
  5. Version of Record published: December 20, 2022 (version 2)

Copyright

© 2022, Szego et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Eva M Szego
  2. Laura Malz
  3. Nadine Bernhardt
  4. Angela Rösen-Wolff
  5. Björn H Falkenburger
  6. Hella Luksch
(2022)
Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
eLife 11:e81943.
https://doi.org/10.7554/eLife.81943

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https://doi.org/10.7554/eLife.81943

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