TY - JOUR TI - Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice AU - Szego, Eva M AU - Malz, Laura AU - Bernhardt, Nadine AU - Rösen-Wolff, Angela AU - Falkenburger, Björn H AU - Luksch, Hella A2 - Ye, Keqiang A2 - Zaidi, Mone VL - 11 PY - 2022 DA - 2022/10/31 SP - e81943 C1 - eLife 2022;11:e81943 DO - 10.7554/eLife.81943 UR - https://doi.org/10.7554/eLife.81943 AB - 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. KW - parkinson KW - synuclein KW - neurodegeneration KW - innate immunity KW - neuroinflammation KW - inflammasome JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -