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

• DOI: 10.7554/elife.81943
• Publication Date: 2022-10-31T13:01:03Z
• Authors: Eva M Szego; Laura Malz; Nadine Bernhardt; Angela Rösen-Wolff; Björn H Falkenburger; Hella Luksch
• Keywords: Sting; TANK-binding kinase 1

Stimulator of interferon genes (STING) is activated after detection cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral sclerosis, and pathway has been implicated in pathogenesis further neurodegenerative diseases. To test whether activation sufficient to induce neurodegeneration, we analysed a mouse model that expresses constitutively active variant N153S. In this model, focused on dopaminergic neurons, which particularly sensitive stress represent circumscribed population can be precisely quantified. adult mice expressing N153S STING, number neurons was smaller than controls, density axon terminals concentration dopamine striatum. We also observed alpha-synuclein pathology lower synaptic puncta. Neuroinflammation quantified staining astroglia microglia, measuring mRNAs, proteins nuclear translocation transcription factors. These neuroinflammatory markers were already elevated juvenile although at age still unaffected, thus preceding degeneration neurons. More blunted deficient for inflammasomes signalling type I interferons. Neurodegeneration, however, both mice. Collectively, these findings demonstrate chronic cause Targeting could therefore beneficial Parkinson’s disease