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Dietary intake of α-ketoglutarate ameliorates α-synuclein pathology in mouse models of Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is a progressive movement disorder characterized by dopaminergic (DA) neuron degeneration and the existence of Lewy bodies formed by misfolded α-synuclein. Emerging evidence supports the benefits of dietary interventions in PD due to their safety and practicality. Previously, dietary intake of α-ketoglutarate (AKG) was proved to extend the lifespan of various species and protect mice from frailty. However, the mechanism of dietary AKG’s effects in PD remains undetermined. In the present study, we report that an AKG-based diet significantly ameliorated α-synuclein pathology, and rescued DA neuron degeneration and impaired DA synapses in adeno-associated virus (AAV)-loaded human α-synuclein mice and transgenic A53T α-synuclein (A53T α-Syn) mice. Moreover, AKG diet increased nigral docosahexaenoic acid (DHA) levels and DHA supplementation reproduced the anti-α-synuclein effects in the PD mouse model. Our study reveals that AKG and DHA induced microglia to phagocytose and degrade α-synuclein via promoting C1q and suppressed pro-inflammatory reactions. Furthermore, results indicate that modulating gut polyunsaturated fatty acid metabolism and microbiota Lachnospiraceae_NK4A136_group in the gut-brain axis may underlie AKG’s benefits in treating α-synucleinopathy in mice. Together, our findings propose that dietary intake of AKG is a feasible and promising therapeutic approach for PD.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the supplementary files, and the RNA-seq data can be publicly found at the Gene Expression Omnibus database under accession number GSE214446. Requests for any materials in this study should be directed to Yunlong Zhang and obtained through an MTA.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82174468 to Y.L.Z., No. 81870856, 81870992, 82071416 to P.Y.X., No. 82101325 to W.L.Z.), the Science and Technology Planning Project of Guangzhou (No. 201904010238 to Y.L.Z.), Guangzhou Medical University Discipline Construction Funds (Basic Medicine, No. JCXKJS2022A09 to Y.L.Z.), Central government guiding local science and technology development projects (No. ZYYD2022C17 to P.Y.X.), Key Research and Development Program of Guangzhou (No. 2023B03J0631 to P.Y.X.), Municipal University (Faculty) joint funding project (No. 202102010010 to P.Y.X.), Guangdong Basic and Applied Basic Research Foundation (No. 2022B1515230004 to P.Y.X.), and the China Postdoctoral Science Foundation (No. 2021M700951 to W.L.Z.).

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Author notes

  1. Wenlong Zhang, Liuyan Ding and Mengran Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China

    Wenlong Zhang, Liuyan Ding, Hengxu Mao & Pingyi Xu

  2. Key Laboratory of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Wenlong Zhang, Liuyan Ding, Mengran Zhang, Shaohui Zheng, Runfang Ma, Junwei Gong & Yunlong Zhang

  3. School of Life Sciences, Westlake University, Hangzhou, 310024, China

    Mengran Zhang, Shaohui Zheng, Runfang Ma & Yunlong Zhang

  4. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, China

    Mengran Zhang, Shaohui Zheng, Runfang Ma & Yunlong Zhang

  5. Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China

    Huaxi Xu

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  1. Wenlong Zhang
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Contributions

YLZ designed the research. WLZ and MRZ performed the Western blotting. LYD and RFM carried out the immunostaining assays. JWG and SHZ injected the AAVs and performed the behavioral tests. HXM prepared and provided the human PFF. YLZ, WLZ, LYD and MRZ analyzed the data. YLZ wrote the manuscript. PYX and HXX discussed the manuscript. All authors read and commented on it.

Corresponding authors

Correspondence to Pingyi Xu or Yunlong Zhang.

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Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The animal study was approved by the guidelines of the Institutional Animal Care and Use Committee of the Guangzhou Medical University and in line with the National Institutes of Health guidelines on the care and use of animals (NIH Publications No. 8023, revised 1978).

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Zhang, W., Ding, L., Zhang, M. et al. Dietary intake of α-ketoglutarate ameliorates α-synuclein pathology in mouse models of Parkinson’s disease. Cell. Mol. Life Sci. 80, 155 (2023). https://doi.org/10.1007/s00018-023-04807-7

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