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

Acta Pharmacologica Sinica volume 47, pages 860–875 (2026)Cite this article

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.

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Fig. 1: Microglia are activated to develop a proinflammatory phenotype within the substantia nigra of α-syn-A53T-1w mice.
Fig. 2: Microglial depletion leads to a substantial reduction in α-synuclein levels within the substantia nigra of α-syn-A53T-1w mice.
Fig. 3: Microglial depletion significantly ameliorates the dysregulation of iron-related proteins in the substantia nigra of α-syn-A53T-1w mice.
Fig. 4: Microglial depletion significantly attenuates cell senescence signaling within the substantia nigra of α-syn-A53T-1w mice.
Fig. 5: Potential signaling pathway associated with α-syn-A53T-induced cellular senescence.
Fig. 6: Potential modulatory effects of α-syn-A53T on the TNF signaling pathway.
Fig. 7: NLRP3 knockout significantly ameliorates the pathological changes induced by α-syn-A53T in the substantia nigra of α-syn-A53T-1w mice.
Fig. 8: NLRP3 knockout significantly reduces the levels of cell senescence-related proteins in the nigral dopaminergic neurons of α-syn-A53T-1w mice.

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References

  1. Shen QQ, Jv XH, Ma XZ, Li C, Liu L, Jia WT, et al. Cell senescence induced by toxic interaction between alpha-synuclein and iron precedes nigral dopaminergic neuron loss in a mouse model of Parkinson’s disease. Acta Pharmacol Sin. 2024;45:268–81.

    Article  CAS  PubMed  Google Scholar 

  2. Chinta SJ, Woods G, Demaria M, Rane A, Zou Y, McQuade A, et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 2018;22:930–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Verma DK, Seo BA, Ghosh A, Ma SX, Hernandez-Quijada K, Andersen JK, et al. Alpha-synuclein preformed fibrils induce cellular senescence in Parkinson’s disease models. Cells. 2021;10:1694–714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hong B, Ohtake Y, Itokazu T, Yamashita T. Glial senescence enhances alpha-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction. Cell Death Discov. 2024;10:50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Riessland M, Kolisnyk B, Kim TW, Cheng J, Ni J, Pearson JA, et al. Loss of SATB1 induces p21-dependent cellular senescence in post-mitotic dopaminergic neurons. Cell Stem Cell. 2019;25:514–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Scott KM, Williams-Gray CH. Targeting aged astrocytes may be a new therapeutic strategy in Parkinson’s disease. Mov Disord. 2018;33:758–9.

    Article  PubMed  Google Scholar 

  7. Scheiblich H, Eikens F, Wischhof L, Opitz S, Jungling K, Cserep C, et al. Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. Neuron. 2024;112:3106–25 e8.

    Article  CAS  PubMed  Google Scholar 

  8. Li Y, Xia X, Wang Y, Zheng JC. Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease. J Neuroinflammation. 2022;19:248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Isik S, Yeman Kiyak B, Akbayir R, Seyhali R, Arpaci T. Microglia mediated neuroinflammation in Parkinson’s disease. Cells. 2023;12:1012.

  10. Rim C, You MJ, Nahm M, Kwon MS. Emerging role of senescent microglia in brain aging-related neurodegenerative diseases. Transl Neurodegener. 2024;13:10.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chen LL, Wang YB, Song JX, Deng WK, Lu JH, Ma LL, et al. Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy. Autophagy. 2017;13:1969–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen L, Ma Y, Ma X, Liu L, Jv X, Li A, et al. TFEB regulates cellular labile iron and prevents ferroptosis in a TfR1-dependent manner. Free Radic Biol Med. 2023;208:445–57.

    Article  CAS  PubMed  Google Scholar 

  13. Mi XQ, Liu BC, Qu L, Yuan Y, Li H, Xu AY, et al. Intranasal iron administration induces iron deposition, immunoactivation, and cell-specific vulnerability in the olfactory bulb of C57BL/6 mice. Zool Res. 2025;46:209–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hendrickx DAE, van Eden CG, Schuurman KG, Hamann J, Huitinga I. Staining of HLA-DR, Iba1, and CD68 in human microglia reveals partially overlapping expression depending on cellular morphology and pathology. J Neuroimmunol. 2017;309:12–22.

    Article  CAS  PubMed  Google Scholar 

  15. Song N, Chen L, Xie J. Alpha-synuclein handling by microglia: activating, combating, and worsening. Neurosci Bull. 2021;37:751–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Thi Lai T, Kim YE, Nguyen LTN, Thi Nguyen T, Kwak IH, Richter F, et al. Microglial inhibition alleviates alpha-synuclein propagation and neurodegeneration in Parkinson’s disease mouse model. NPJ Parkinson’s Dis. 2024;10:32.

    Article  Google Scholar 

  17. Bishop GM, Dang TN, Dringen R, Robinson SR. Accumulation of non-transferrin-bound iron by neurons, astrocytes, and microglia. Neurotox Res. 2011;19:443–51.

    Article  CAS  PubMed  Google Scholar 

  18. Ryan SK, Zelic M, Han Y, Teeple E, Chen L, Sadeghi M, et al. Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration. Nat Neurosci. 2023;26:12–26.

    Article  CAS  PubMed  Google Scholar 

  19. Chen L, Shen Q, Liu Y, Zhang Y, Sun L, Ma X, et al. Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases. Signal Transduct Target Ther. 2025;10:31.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Reinert A, Morawski M, Seeger J, Arendt T, Reinert T. Iron concentrations in neurons and glial cells with estimates on ferritin concentrations. BMC Neurosci. 2019;20:25.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hu L, Dong C, Wang Z, He S, Yang Y, Zi M, et al. A rationally designed fluorescence probe achieves highly specific and long-term detection of senescence in vitro and in vivo. Aging Cell. 2023;22:e13896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kaur S, Coulombe Y, Ramdzan ZM, Leduy L, Masson JY, Nepveu A. Special AT-rich sequence-binding protein 1 (SATB1) functions as an accessory factor in base excision repair. J Biol Chem. 2016;291:22769–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu KM, Xu QH, Liu YQ, Feng YW, Han SD, Zhang YR, et al. Neuronal FAM171A2 mediates alpha-synuclein fibril uptake and drives Parkinson’s disease. Science. 2025;387:892–900.

    Article  CAS  PubMed  Google Scholar 

  24. Russo T, Kolisnyk B, Aswathy BS, Plessis-Belair J, Kim TW, Martin J, et al. The SATB1-MIR22-GBA axis mediates glucocerebroside accumulation inducing a cellular senescence-like phenotype in dopaminergic neurons. Aging Cell. 2024;23:e14077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stokholm MG, Iranzo A, Ostergaard K, Serradell M, Otto M, Svendsen KB, et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol. 2017;16:789–96.

    Article  PubMed  Google Scholar 

  26. Ma XZ, Chen LL, Qu L, Li H, Wang J, Song N, et al. Gut microbiota-induced CXCL1 elevation triggers early neuroinflammation in the substantia nigra of Parkinsonian mice. Acta Pharmacol Sin. 2024;45:52–65.

    Article  PubMed  Google Scholar 

  27. Choi I, Zhang Y, Seegobin SP, Pruvost M, Wang Q, Purtell K, et al. Microglia clear neuron-released alpha-synuclein via selective autophagy and prevent neurodegeneration. Nat Commun. 2020;11:1386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yuan J, Liu H, Zhang H, Wang T, Zheng Q, Li Z. Controlled activation of TRPV1 channels on microglia to boost their autophagy for clearance of alpha-synuclein and enhance therapy of Parkinson’s disease. Adv Mater. 2022;34:e2108435.

    Article  PubMed  Google Scholar 

  29. Pei CS, Hou XO, Ma ZY, Tu HY, Qian HC, Li Y, et al. alpha-synuclein disrupts microglial autophagy through STAT1-dependent suppression of Ulk1 transcription. J Neuroinflammation. 2024;21:275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tu HY, Yuan BS, Hou XO, Zhang XJ, Pei CS, Ma YT, et al. alpha-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson’s disease. Aging Cell. 2021;20:e13522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q, et al. Microglial exosomes facilitate alpha-synuclein transmission in Parkinson’s disease. Brain. 2020;143:1476–97.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Xia Y, Zhang G, Kou L, Yin S, Han C, Hu J, et al. Reactive microglia enhance the transmission of exosomal alpha-synuclein via toll-like receptor 2. Brain. 2021;144:2024–37.

    Article  PubMed  Google Scholar 

  33. Jiao L, Li X, Luo Y, Wei J, Ding X, Xiong H, et al. Iron metabolism mediates microglia susceptibility in ferroptosis. Front Cell Neurosci. 2022;16:995084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang J, Song N, Jiang H, Wang J, Xie J. Pro-inflammatory cytokines modulate iron regulatory protein 1 expression and iron transportation through reactive oxygen/nitrogen species production in ventral mesencephalic neurons. Biochim Biophys Acta. 2013;1832:618–25.

    Article  CAS  PubMed  Google Scholar 

  36. Wang J, Bi M, Liu H, Song N, Xie J. The protective effect of lactoferrin on ventral mesencephalon neurons against MPP+ is not connected with its iron-binding ability. Sci Rep. 2015;5:10729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fillebeen C, Ruchoux MM, Mitchell V, Vincent S, Benaissa M, Pierce A. Lactoferrin is synthesized by activated microglia in the human substantia nigra, and its synthesis by the human microglial CHME cell line is upregulated by tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment. Brain Res Mol Brain Res. 2001;96:103–13.

    Article  CAS  PubMed  Google Scholar 

  38. Singh J, Habean ML, Panicker N. Inflammasome assembly in neurodegenerative diseases. Trends Neurosci. 2023;46:814–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fan Z, Pan YT, Zhang ZY, Yang H, Yu SY, Zheng Y, et al. Systemic activation of NLRP3 inflammasome and plasma alpha-synuclein levels are correlated with motor severity and progression in Parkinson’s disease. J Neuroinflammation. 2020;17:11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Senkevich K, Liu L, Alvarado CX, Leonard HL, Nalls MA, Global Parkinson’s Genetics P, et al. Lack of genetic evidence for NLRP3 inflammasome involvement in Parkinson’s disease pathogenesis. NPJ Parkinson’s Dis. 2024;10:145.

    Article  CAS  Google Scholar 

  41. Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, et al. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018;10:eaah4066.

  42. Pike AF, Varanita T, Herrebout MAC, Plug BC, Kole J, Musters RJP, et al. alpha-synuclein evokes NLRP3 inflammasome-mediated IL-1beta secretion from primary human microglia. Glia. 2021;69:1413–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zheng R, Yan Y, Dai S, Ruan Y, Chen Y, Hu C, et al. ASC specks exacerbate alpha‑synuclein pathology via amplifying NLRP3 inflammasome activities. J Neuroinflammation. 2023;20:26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Haque ME, Akther M, Jakaria M, Kim IS, Azam S, Choi DK. Targeting the microglial NLRP3 inflammasome and its role in Parkinson’s disease. Mov Disord. 2020;35:20–33.

    Article  CAS  PubMed  Google Scholar 

  45. Panicker N, Kam TI, Wang H, Neifert S, Chou SC, Kumar M, et al. Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease. Neuron. 2022;110:2422–37.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McFarthing K, Buff S, Rafaloff G, Pitzer K, Fiske B, Navangul A, et al. Parkinson’s disease drug therapies in the clinical trial pipeline: 2024 update. J Parkinson’s Dis. 2024;14:899–912.

    Article  Google Scholar 

  47. Feng J, Liu H, Jiang K, Gong X, Huang R, Zhou C, et al. Enhanced oxidative stress aggravates BLM-induced pulmonary fibrosis by promoting cellular senescence through enhancing NLRP3 activation. Life Sci. 2024;358:123128.

    Article  CAS  PubMed  Google Scholar 

  48. Kim JW, Nam SA, Koh ES, Kim HW, Kim S, Woo JJ, et al. The impairment of endothelial autophagy accelerates renal senescence by ferroptosis and NLRP3 inflammasome signaling pathways with the disruption of endothelial barrier. Antioxidants (Basel). 2024;13:886.

  49. Valenzuela-Arzeta IE, Soto-Rojas LO, Flores-Martinez YM, Delgado-Minjares KM, Gatica-Garcia B, Mascotte-Cruz JU, et al. LPS triggers acute neuroinflammation and Parkinsonism involving NLRP3 inflammasome pathway and mitochondrial ci dysfunction in the rat. Int J Mol Sci. 2023;24:4628.

  50. Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S, et al. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING. Proc Natl Acad Sci USA. 2021;118:e2011226118.

  51. Chen PY, Yen JC, Liu TT, Chen ST, Wang SJ, Chen SP. Neuronal NLRP3 inflammasome mediates spreading depolarization-evoked trigeminovascular activation. Brain. 2023;146:2989–3002.

    Article  PubMed  Google Scholar 

  52. Xu W, Huang Y, Zhou R. NLRP3 inflammasome in neuroinflammation and central nervous system diseases. Cell Mol Immunol. 2025;22:341–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, et al. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PLoS One. 2015;10:e0130624.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (32471049, 32170984) to Jun-xia Xie, Natural Science Foundation of Shandong Province-Outstanding Youth Foundation (ZR2020YQ23, ZR2024MC153) and Qingdao Natural Science Foundation (24-4-4-zrjj-133-jch) to Lei-lei Chen, and Natural Science Foundation of Shandong Province (ZR2025QC905) to Qing-qing Shen. These fundings are involved in the data collection, analysis, and publication.

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  1. These authors contributed equally: Lei-lei Chen, Qing-qing Shen, Li-ping Sun

Authors and Affiliations

  1. Institute of Brain Science and Disease, Qingdao University, Qingdao, 266071, China

    Lei-lei Chen, Qing-qing Shen, Li-ping Sun, Yu-xiang Song, Wen-ting Jia, Le Qu & Jun-xia Xie

  2. Shandong Provincial Neuroscience Research Center, Qingdao University, Qingdao, 266071, China

    Lei-lei Chen, Qing-qing Shen, Li-ping Sun, Yu-xiang Song, Wen-ting Jia, Le Qu & Jun-xia Xie

  3. Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, 266071, China

    Lei-lei Chen, Qing-qing Shen, Li-ping Sun, Yu-xiang Song, Wen-ting Jia, Le Qu & Jun-xia Xie

  4. Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, 266071, China

    Lei-lei Chen, Qing-qing Shen, Li-ping Sun, Yu-xiang Song, Wen-ting Jia, Le Qu & Jun-xia Xie

  5. Medical School, Linyi University, Linyi, 276000, China

    Qing-qing Shen

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LLC, QQS, LPS, YXS were involved in experimental research and data analysis. WTJ and LQ involved in methodology. JXX and LLC were involved in conceptualization, methodology, writing, and supervision. All authors have read and approved the final manuscript.

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Correspondence to Lei-lei Chen or Jun-xia Xie.

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Chen, Ll., Shen, Qq., Sun, Lp. et al. 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 47, 860–875 (2026). https://doi.org/10.1038/s41401-025-01691-8

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