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Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson’s disease

Molecular Psychiatry volume 28, pages 1337–1350 (2023)Cite this article

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Abstract

Gut dysbiosis contributes to Parkinson’s disease (PD) pathogenesis. Gastrointestinal disturbances in PD patients, along with gut leakage and intestinal inflammation, take place long before motor disorders. However, it remains unknown what bacterial species in gut microbiomes play the key role in driving PD pathogenesis. Here we show that Helicobacter hepaticus (H. hepaticus), abundant in gut microbiota from rotenone-treated human α-Synuclein gene (SNCA) transgenic mice and PD patients, initiates α-Synuclein pathology and motor deficits in an AEP-dependent manner in SNCA mice. Chronic Dextran sodium sulfate (DSS) treatment, an inflammatory inducer in the gut, activates AEP (asparagine endopeptidase) that cleaves α-Synuclein N103 and triggers its aggregation, promoting inflammation in the gut and the brain and motor defects in SNCA mice. PD fecal microbiota transplant or live H. hepaticus administration into antibiotics cocktail (Abx)-pretreated SNCA mice induces α-Synuclein pathology, inflammation in the gut and brain, and motor dysfunctions, for which AEP is indispensable. Hence, Helicobacter hepaticus enriched in PD gut microbiomes may facilitate α-Synuclein pathologies and motor impairments via activating AEP.

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Fig. 1: Microbiome analysis in SNCA and SNCA/AEP KO mouse stool reveals an alteration in the microbial community.
Fig. 2: Microbiota profiling, comparative biomarker discovery and correlation analysis.
Fig. 3: DSS induces constipation and PD-like pathogenesis in the gut of SNCA mice.
Fig. 4: PD patients FMT elicits dopaminergic loss, inflammation and motor disorders in Abx-pretreated SNCA mice.
Fig. 5: Active H. Hepaticus triggers dopaminergic loss, inflammation and motor disorders in Abx-pretreated SNCA mice.
Fig. 6: Active H. Hepaticus triggers PD pathologies and motor disorders in SNCA mice.

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Acknowledgements

This study was supported in part by the Emory Gnotobiotic Animal (EGAC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities; the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities; as well as Emory HPLC Bioanalytical Core (EHBC), which was supported by the Department of Pharmacology, Emory University School of Medicine. Drs. Zhi-Dong Jiang and Herbert L. Dupont from University of Texas School of Public Health and Medical School, Baylor St. Luke’s Medical Center, Baylor College of Medicine, Houston, TX, USA provided PD and age-matched HC fecal samples.

Funding

This work was supported by a grant from the National Institute of Health (R01, AG065177) to SSK. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378 and by Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2021R1F1A1063591).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Eun Hee Ahn, Xia Liu, Seong Su Kang & Keqiang Ye

  2. Department of Physiology, College of Medicine, Hallym University, Hallymdaehak-gil, Chuncheon-si, Gangwon-Do, 24252, South Korea

    Eun Hee Ahn

  3. Microbiology, Immunology & Molecular Genetics, University of Kentucky, Office - MN 376, Medical Science Building, 800 Rose Street, Lexington, KY, USA

    Ashfaqul M. Alam

  4. Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, 518055, Guangdong, China

    Keqiang Ye

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Contributions

KY conceived the project, designed the experiments, analyzed the data and wrote the manuscript. EHA, SSK and AMA designed and performed most of the experiments and analyzed the data. XL conducted genotype and breed the transgenic mice. AMA assisted with data analysis and interpretation and critically read the manuscript.

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Correspondence to Seong Su Kang or Keqiang Ye.

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The experimental protocol was approved by the Emory University Institutional Animal Care and Ethical Committee.

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Ahn, E.H., Liu, X., Alam, A.M. et al. Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson’s disease. Mol Psychiatry 28, 1337–1350 (2023). https://doi.org/10.1038/s41380-022-01910-2

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