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The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson’s disease via LCN2-dependent astrocyte senescence

Cell Death & Differentiation volume 30, pages 2280–2292 (2023)Cite this article

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Abstract

Recent studies provide clues that astrocyte senescence is correlated with Parkinson’s disease (PD) progression, while little is known about the molecular basis for astrocyte senescence in PD. Here, we found that cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) was upregulated in senescent astrocytes of PD and aged mice. Strikingly, deletion of astrocytic cGAS significantly prevented senescence of astrocytes and neurodegeneration. Furthermore, we identified LCN2 as the effector of cGAS-STING signal by RNA-Seq analysis. Genetic manipulation of LCN2 expression proved the regulation of cGAS-STING-LCN2 axis in astrocyte senescence. Additionally, YY1 was discovered as the transcription factor of LCN2 by chromatin immunoprecipitation. Binding of STING to YY1 impedes nuclear translocation of YY1. Herein, we determine the involvement of the cGAS-STING-YY1-LCN2 signaling cascade in the control of astrocyte senescence and PD progression. Together, this work fills the gap in our understanding of astrocyte senescence, and provides potential targets for delaying PD progression.

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Fig. 1: cGAS-STING signal is activated in senescent astrocytes of MPTP treated mice and aged mice.
Fig. 2: cGAS-STING knockdown prevents senescence of astrocytes in vitro.
Fig. 3: Astrocytic cGAS ablation alleviates PD like pathology via delay of the senescence of astrocytes in MPTP treated mice.
Fig. 4: Identification of LCN2 as an effector target for cGAS-STING-mediated astrocyte senescence.
Fig. 5: STING directly binds to YY1 and prevents YY1 nuclear translocation to increase LCN2 transcription.
Fig. 6: LCN2 is required for cGAS-STING-mediated astrocyte senescence and neurodegeneration in MPTP treated mice.
Fig. 7: cGAS-STING-LCN2 pathway mediates age-related neurodegeneration in aged mice.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the grants from the National Key R&D Program of China (No. 2021ZD0202903), the National Natural Science Foundation of China (No. 82273906, No. 81922066, No. 82173797 and No. 81991523).

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Authors and Affiliations

  1. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, PR China

    Si-Yuan Jiang, Tian Tian, Hang Yao, Xiao-Mei Xia, Cong Wang, Lei Cao, Gang Hu, Ren-Hong Du & Ming Lu

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Contributions

ML conceived and designed the study. RHD designed the study and wrote the paper. SYJ, TT, HY, XMX and CW performed the experiments and analyzed the data. Gang Hu and LC revised the paper. All authors read and approved the final manuscript

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Correspondence to Ren-Hong Du or Ming Lu.

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The animals used in our study were treated in accordance with protocols approved by the Institutional Animal Care and Use Committee of Nanjing Medical University.

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Jiang, SY., Tian, T., Yao, H. et al. The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson’s disease via LCN2-dependent astrocyte senescence. Cell Death Differ 30, 2280–2292 (2023). https://doi.org/10.1038/s41418-023-01216-y

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