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.
| Original language | English |
|---|---|
| Pages (from-to) | 1337-1350 |
| Number of pages | 14 |
| Journal | Molecular Psychiatry |
| Volume | 28 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2023 |
Bibliographical note
Funding Information: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 Information:
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 Information:
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).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
