Abstract
Cell senescence has been implicated in the pathology of Parkinson’s disease (PD). Both abnormal α-synuclein aggregation and iron deposition are suggested to be the triggers, facilitators, and aggravators during the development of PD. In this study, we investigated the involvement of α-synuclein and iron in the process of cell senescence in a mouse model of PD. In order to overexpress α-syn-A53T in the substantia nigra pars compacta (SNpc), human α-syn-A53T was microinjected into both sides of the SNpc in mice. We found that overexpression of α-syn-A53T for one week induced significant pro-inflammatory senescence-associated secretory phenotype (SASP), increased cell senescence-related proteins (β-gal, p16, p21, H2A.X and γ-H2A.X), mitochondrial dysfunction accompanied by dysregulation of iron-related proteins (L-ferritin, H-ferritin, DMT1, IRP1 and IRP2) in the SNpc. In contrast, significant loss of nigral dopaminergic neurons and motor dysfunction were only observed after overexpression of α-syn-A53T for 4 weeks. In PC12 cells stably overexpressing α-syn-A53T, iron overload (ferric ammonium citrate, FAC, 100 μM) not only increased the level of reactive oxygen species (ROS), p16 and p21, but also exacerbated the processes of oxidative stress and cell senescence signalling induced by α-syn-A53T overexpression. Interestingly, reducing the iron level with deferoxamine (DFO) or knockdown of transferrin receptor 1 (TfR1) significantly improved both the phenotypes and dysregulated proteins of cell senescence induced by α-syn-A53T overexpression. All these evidence highlights the toxic interaction between iron and α-synuclein inducing cell senescence, which precedes nigral dopaminergic neuronal loss in PD. Further investigation on cell senescence may yield new therapeutic agents for the prevention or treatment of PD.
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Acknowledgements
This work was supported by grants from National Natural Science Foundation of China (32170984), Natura Science Foundation of Shandong Province (ZR2020YQ23, ZR2023QH110), and Qingdao Postdoctoral Research Project (QDBSH20220202204).
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QQS, XHJ, XZM, CL, and LL 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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Shen, Qq., Jv, Xh., Ma, Xz. et al. Cell senescence induced by toxic interaction between α-synuclein and iron precedes nigral dopaminergic neuron loss in a mouse model of Parkinson’s disease. Acta Pharmacol Sin 45, 268–281 (2024). https://doi.org/10.1038/s41401-023-01153-z
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DOI: https://doi.org/10.1038/s41401-023-01153-z
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