2. Academic Validation
  3. NLRP3 facilitates α-synuclein-induced dopaminergic neuronal senescence in a mouse model of Parkinson's disease through SATB1/DNA damage/p21 signaling pathway

NLRP3 facilitates α-synuclein-induced dopaminergic neuronal senescence in a mouse model of Parkinson's disease through SATB1/DNA damage/p21 signaling pathway

  • Acta Pharmacol Sin. 2026 Jan 1. doi: 10.1038/s41401-025-01691-8.
Lei-Lei Chen # 1 2 3 4,  Qing-Qing Shen # 5 6 7 8 9,  Li-Ping Sun # 5 6 7 8,  Yu-Xiang Song 5 6 7 8,  Wen-Ting Jia 5 6 7 8,  Le Qu 5 6 7 8,  Jun-Xia Xie 10 11 12 13
Affiliations

Affiliations

  • 1 Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China. [email protected].
  • 2 Shandong Provincial Neuroscience Research Center, Qingdao University, Qingdao, 266071, China. [email protected].
  • 3 Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, 266071, China. [email protected].
  • 4 Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, 266071, China. [email protected].
  • 5 Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China.
  • 6 Shandong Provincial Neuroscience Research Center, Qingdao University, Qingdao, 266071, China.
  • 7 Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, 266071, China.
  • 8 Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, 266071, China.
  • 9 Medical School, Linyi University, Linyi, 276000, China.
  • 10 Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China. [email protected].
  • 11 Shandong Provincial Neuroscience Research Center, Qingdao University, Qingdao, 266071, China. [email protected].
  • 12 Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, 266071, China. [email protected].
  • 13 Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, 266071, China. [email protected].
  • # Contributed equally.
PMID: 41476182 DOI: 10.1038/s41401-025-01691-8
Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of nigral dopaminergic neurons and abnormal accumulation of α-synuclein. Our recent study has shown 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. In this study, we identified the cell type susceptible to α-synuclein-induced cellular senescence in the substantia nigra and investigated the specific role of microglia with a particular focus on the NLRP3 inflammasome. PD mouse model was established by bilateral microinjection of viaAAV2/9 vectors encoding human α-syn-A53T into the SNpc to overexpress human mutant α-synuclein-A53T. We showed that overexpression of α-synuclein-A53T (α-syn-A53T) for 1 week not only induced a pro-inflammatory phenotype in nigral microglia but also led to the acquisition of a senescent state in a subset of microglial cells. Depletion of microglia by administration of the CSF1R inhibitor PLX5622 (1200 ppm) in diet for 1 week significantly attenuated α-synuclein Aggregation, iron dysregulation and cellular senescence in the substantia nigra of PD mouse model. Transcriptomic and immunostaining analyses revealed that α-syn-A53T promoted senescence in nigral dopaminergic neurons via the SATB1/DNA damage/p21 signaling pathway, evidenced by reduced SATB1 expression along with increased levels of γ-H2A.X and p21 in TH-positive dopaminergic neurons within the substantia nigra. Moreover, genetic knockout of NLRP3 effectively mitigated α-syn-A53T-induced cellular senescence in these neurons by suppressing the SATB1/DNA damage/p21 signaling pathway. These results 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 mitigate neuronal senescence and subsequent neurodegeneration.

Keywords

NLRP3; Parkinson’s disease; cellular senescence; dopaminergic neurons; microglia; α-synuclein.

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