Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
- TU Dresden, Germany
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
Björn H Falkenburger
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.
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.
Reviewing Editor
- Keqiang Ye, Chinese Academy of Sciences, China
Publication history
- Preprint posted: February 4, 2022 (view preprint)
- Received: August 2, 2022
- Accepted: October 31, 2022
- Accepted Manuscript published: October 31, 2022 (version 1)
- 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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Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice
eLife 11:e81943.
https://doi.org/10.7554/eLife.81943
Further reading
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Background: A salutary effect of treatments for Gaucher disease (GD) has been reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT), and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity or anti-drug antibodies.
Objective: Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center.
Methods: Longitudinal follow-ups of 155 GD patients between 2001 and 2021, were analyzed for episodes of AVN on therapy, type of therapy, GBA1 genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment.
Results: The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI,1.5 - 67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI,1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001).
Conclusions: There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found increased risk of AVN was related to GBA genotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization.
Funding: LSD Training Fellowship from Sanofi to MB.
