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

Abstract

The innate immune system can protect against certain aspects of neurodegenerative diseases, but also contribute to disease progression. Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the defense against viral pathogens, activating type I interferon and NF-kB/inflammasome signaling. In order to specifically test the relevance of this pathway for the degeneration of dopaminergic neurons in Parkinson's disease, we studied a mouse model with heterozygous expression of the constitutively active STING variant N153S. 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. Neuroinflammatory markers were already elevated in juvenile mice, thus preceding the degeneration of dopaminergic neurons. Inflammation and neurodegeneration were blunted in mice deficient for signaling by type I interferons or inflammasomes, but not suppressed completely. Collectively, these findings demonstrate that chronic activation of the STING innate immunity pathway is sufficient to cause degeneration of dopaminergic neurons. This pathway could be targeted therapeutically.

Supramolecular organizing centers at the interface of inflammation and neurodegeneration

“…Szegö and coworkers corroborated this finding in a recent preprint where they showed that chronic activation of STING causes degeneration of dopaminergic neurons. Constitutively, active variant STING knock-in mice demonstrated the accumulation of pathological α-synuclein ( 154 ). STING activation may contribute to neurodegeneration in patients with a rare α-synucleinopathy, multiple-system atrophy ( 155 ).…”