NLRP3 FACILITATES Α-SYNUCLEIN-INDUCED NIGRAL DOPAMINERGIC NEURONAL SENESCENCE THROUGH SATB1/DNA DAMAGE/P21 SIGNALING PATHWAY

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of nigral dopaminergic neurons and the abnormal accumulation of α-synuclein. Our previous research has demonstrated that α-synuclein induces cellular senescence prior to the loss of dopaminergic neurons and the onset of motor dysfunction. Microglia are known to contribute to dopaminergic neurodegeneration, primarily through NLRP3-mediated neuroinflammatory mechanism or by facilitating the propagation of α-synuclein. However, the specific role of microglia in the senescence of dopaminergic neurons in the context of PD remains poorly understood. In this study, we found that overexpression of α-synuclein-A53T (α-syn-A53T) for one week not only induces a pro-inflammatory phenotype in nigral microglia but also leads to the acquisition of a senescent state in a subset of microglial cells. Depletion of microglial through administration of PLX5622 significantly attenuates α-synuclein aggregation, iron dysregulation, and cellular senescence in the substantia nigra of PD mouse model. Transcriptomic analysis and immunostaining further revealed that α-syn-A53T promotes senescence in nigral dopaminergic neurons via the SATB1/DNA damage/p21 signaling pathway, as with evidenced by reduced SATB1 expression, along with increased levels of γ-H2A.X and p21 in the tyrosine hydroxylase (TH)-positive dopaminergic neurons within the substantia nigra. Moreover, genetic knockout of NLRP3 effectively mitigates α-syn-A53T-induced cellular senescence in these neurons by suppressing the SATB1/DNA damage/p21 signaling pathway. These findings highlight the critical role of microglia in promoting dopaminergic neuronal senescence and suggest that NLRP3 may serve as a promising therapeutic target for early intervention in PD to mitigated neuronal senescence and subsequent neurodegeneration.