Autonomous STING signaling in Purkinje cells drives neurodegeneration independent of type I interferon

STING signaling is emerging as a critical component of neurodegenerative diseases. While microglial STING-type I interferon (IFN-I) signaling is well-established, the role of STING signaling in neurons remains unclear. Here, we show that the STING protein is expressed in Purkinje cells of the cerebellum. Selective activation of STING signaling only in Purkinje cells using a conditional constitutively active N153S allele results in progressive neuronal loss and cerebellar atrophy, astrogliosis, but no microgliosis, leading to severe motor impairments in mice. Surprisingly, Purkinje cell STING activation does not induce IFN-I response. IFN-I receptor (Ifnar1) knockout also does not mitigate Purkinje cell STING-mediated neurodegeneration. Electrophysiological analyses reveal that Purkinje cell STING signaling reduces autonomous firing, which is essential for pace-making and neuronal function. Together, these findings demonstrate the physiological significance of IFN-independent STING function in Purkinje neurons and highlight its divergence from microglial STING signaling.