Impaired proteasome induces mitochondrial DNA release to activate the cGAS-STING signaling pathway and cause necroptosis in mouse brain

Impaired proteasome function is consistently associated with many neurodegenerative disorders, including Alzheimer's disease (AD), showing neuroinflammation and neurodegeneration; however, how impaired proteasome causes neuroinflammation and neuronal death remains less understood. Here, we studied the effect of impaired proteasome on neuroinflammation and neuronal death in a knockout (KO) mouse model with reduced proteasome activity in the brain. We discovered that impaired proteasome led to the release of mitochondrial dsDNA into the cytosol, activating the cGAS-STING signaling pathway, and upregulating pro-inflammatory cytokines in the KO mouse brain relative to the control brain. Importantly, we also observed reduced brain weight, elevation of the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interactive protein kinases (RIPK) 1 and 3 in the KO mouse brain compared to the control brain, suggesting activation of necroptosis in the KO brains. These data indicate that impaired proteasome activates the cGAS-STING pathway to induce neuroinflammation and neurodegeneration via a necroptotic manner. Our results suggest that neuroinflammation and necroptosis may be generalized factors caused by reduced proteasome activity observed in diverse neurodegenerative disorders.