DNase2a downregulated by the cGAS-STING-IFN-MEF2C pathway prevents α-synuclein ubiquitination via NEDD4 in Parkinson's disease

Background DNase2a, a key enzyme responsible for clearing cytoplasmic double-stranded DNA, prevents cytosolic DNA accumulation. Accumulating evidence suggests that aberrant cytosolic DNA accumulation contributes to Parkinson’s disease (PD) pathogenesis, yet the role of DNase2a in PD remains unclear. Methods We examined the effects of neuronal DNase2a and cytosolic damaged DNA on α-synuclein (α-Syn) accumulation in cultured neurons and male A53T transgenic mice, and investigated the underlying mechanism by which α-Syn modulates DNase2a expression. Results The levels of DNase2a were markedly reduced in the brain of A53T α-Syn transgenic mice, accompanied by increased cytoplasmic DNA accumulation. Decreased neuronal DNase2a led to persistent cytosolic DNA accumulation and suppressed NEDD4-mediated α-Syn ubiquitination and degradation, exacerbating α-Syn accumulation and PD pathology in vitro and in vivo. Moreover, A53T α-Syn further aggravated cytosolic DNA accumulation and then repressed MEF2C-mediated DNase2a transcription via activating the cGAS-STING-IFN pathway, forming a deleterious loop between DNase2a and α-Syn. Consistently, neuronal DNase2a deficiency in WT mice drove α-Syn pathology and dopaminergic neuronal degeneration, leading to motor deficits characteristic of PD, while neuronal DNase2a overexpression in A53T transgenic mice significantly ameliorated motor deficits by reducing α-Syn accumulation and preserving dopaminergic neuron integrity. Conclusions Our findings reveal that DNase2a deficiency disrupts α-Syn degradation and accelerates PD pathogenesis, suggesting that DNase2a is a potential therapeutic target for PD.