LAUSR

Significance It is increasingly recognized that chronic neuroinflammation is causally relevant to neurodegeneration. In Parkinson’s disease (PD), α-synuclein pathology activates inflammatory signaling that disturbs parenchymal homeostasis and disrupts neuron-glia interactions. Herein, we report that the innate immune cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) DNA-sensing pathway is activated in a mouse model of α-synucleinopathy and parkinsonism, leading to type-I interferon activation that precedes the onset of neurodegeneration. Remarkably, STING-deficient mice were protected from dopaminergic neuron loss in this model. We also show that αSyn aggregates can increase STING expression and augment canonical STING activation, suggesting a possible generalized propensity for exaggerated antiviral responses in neurological states with STING elevation. Our results suggest that STING inhibition may be therapeutic in idiopathic PD and possibly other human α-synucleinopathies.