The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson’s disease via LCN2-dependent astrocyte senescence
Open accessAbstract
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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Lipocalin-2 and sclerostin aggravate neuroinflammation and abolish synaptic plasticity, thereby accelerating the progression of Alzheimer's disease, Parkinson's disease and ALS.
“LCN2 and sclerostin aggravate neuroinflammation and abolish synaptic plasticity,304,305 thereby accelerating the progression of AD, PD and ALS.306–308”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [306]
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Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
Jiang, Q., Liu, J., Huang, S., Wang, X.-Y., Chen, X., Liu, G.-H., Ye, K., Song, W., Masters, C. L., Wang, J., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02145-7 · Cited by 165 · see citing works
- Authors
- Jiang, S.-Y., Tian, T., Yao, H., Xia, X.-M., Wang, C., Cao, L., Hu, G., Du, R.-H., & Lu, M.
- Affiliations
- Nanjing Medical University (CN)
- Corresponding author
- Du, Ren-Hong
- Lu, Ming
- Venue
- Cell Death & Differentiation
- Published
- 2023-08-26
- Volume
- 30
- Issue
- 10
- Pages
- 2280-2292
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC10589362
- OpenAlex
- W4386194378
- Cited by
- 123
- References
- 7
- Citations by year
- 2026: 53 · 2025: 47 · 2024: 21 · 2023: 2
- FWCI
- 20.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81991523, 81922066, 82173797)
- National Key R&D Program of China
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Parkinson's disease, astrocyte senescence, cGAS-STING pathway, neutrophil gelatinase-associated lipocalin, YY1 transcription factor, neurodegeneration, aging, senescence-associated inflammation, therapeutic target
- MeSH terms
- Lipocalin-2, STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Astrocytes, Disease Models, Animal, Humans, Membrane Proteins, Mice, Inbred C57BL, Nucleotidyltransferases, Parkinson Disease, Signal Transduction, Cellular Senescence, Disease Progression, YY1 Transcription Factor, Mice
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