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Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson’s disease

Cell Death & Differentiation (2025)Cite this article

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Abstract

Parkinson’s disease (PD) is characterized by the aggregation of misfolded α-synuclein (α-syn) and microglial activation. Galectin-9 (Gal-9) is an immunoregulatory mediator generated by microglia. Here, we found that α-syn fibrils are internalized by microglia and processed by microglial protease AEP, generating α-syn species with enhanced seeding activity and neurotoxicity. Notably, the uptake of α-syn fibrils by microglia leads to increased expression of Gal-9, which further promotes the production of toxic α-syn species via activation of the C/EBPβ/AEP axis. Knockout of Gal-9 attenuates α-syn pathology, dopaminergic neuronal loss, and motor impairments in a mouse model induced by intrastriatal injection of α-syn PFFs. Intrastriatal injection of Gal-9 promoted PD-like phenotypes induced by α-syn PFFs. Furthermore, the detrimental effect of Gal-9 was attenuated by the knockout of AEP. These observations illustrate the key role of Gal-9 in promoting α-syn pathology and neurodegeneration via the C/EBPβ/AEP axis in PD.

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Fig. 1: Microglia milieu promotes the seeding and neurotoxicity of α-syn.
Fig. 2: Microglial AEP cleaves α-syn and enhances its seeding and neurotoxicity.
Fig. 3: Gal-9 promotes microglial AEP activation in vitro.
Fig. 4: Gal-9 and AEP are upregulated in PD.
Fig. 5: Knockout of Gal-9 reduces the spread of α-syn pathology in vivo.
Fig. 6: Knockout of Gal-9 attenuates PD-like motor deficits.
Fig. 7: Gal-9 aggravates α-syn pathology in a PD mouse model.
Fig. 8: Schematic illustration of Gal-9-C/EBPβ/AEP-mediated α-synuclein cleavage in microglia and its contribution to neuronal damage.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82271447 and 81771382 to ZZ, No. 81901090 to LM, No. 82301598 to GZ), the Innovative Research Groups of Hubei Province (2022CFA026 to ZZ), Shenzhen Medical Research Fund (B2404001 to ZZ), and the New 20 Terms of Universities in Jinan grant (No. 202228022 to SL).

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  1. These authors contributed equally: Qinyu Peng, Guoxin Zhang.

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China

    Qinyu Peng, Guoxin Zhang, Xiaodi Guo, Yiming Li, Lina Pan, Lanxia Meng, Jing Xiong & Zhentao Zhang

  2. Department of Academic Research, Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, China

    Xu Xu

  3. Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China

    Sheng Li

  4. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China

    Zhentao Zhang

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  1. Qinyu Peng
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Contributions

ZZ conceived and supervised the project. QP performed the majority of experiments and data analysis, and drafted the manuscript. GZ conducted experiments involving primary neurons, developed methodology, and revised the paper. XG, YL, and LP performed the immunostaining of mouse brain sections. LM and JX helped with the cell culture and animal experiments. XX and SL helped in the analysis and interpretation of data. All authors critically read and revised the manuscript.

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Correspondence to Zhentao Zhang.

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Peng, Q., Zhang, G., Guo, X. et al. Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson’s disease. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01640-2

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