Helicobacter hepaticus augmentation triggers Dopaminergic degeneration and motor disorders in mice with Parkinson's disease
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Updated: Aug 16, 2025
Murine Model for Parkinson's Disease: from 6-OH Dopamine Lesion to Behavioral Test
Published on: January 15, 2010
Eun Hee Ahn1,2, Xia Liu1, Ashfaqul M Alam3
1Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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.
Insights
Helicobacter hepaticus in the gut microbiome drives Parkinson's disease pathology and motor deficits by activating asparagine endopeptidase (AEP). This bacterium initiates alpha-synuclein aggregation and inflammation, crucial steps in Parkinson's disease progression.
Area of Science:
- Neuroscience
- Microbiology
- Gastroenterology
Background:
- Gut dysbiosis and gastrointestinal issues precede motor symptoms in Parkinson's disease (PD).
- The specific gut bacteria driving PD pathogenesis remain largely unidentified.
- Alpha-synuclein (α-Syn) pathology is a hallmark of PD, but its initiation by gut microbes is under investigation.
Purpose of the Study:
- To identify key bacterial species in the gut microbiome that contribute to Parkinson's disease pathogenesis.
- To elucidate the mechanism by which gut bacteria may initiate α-Synuclein pathology and motor deficits in PD.
Main Methods:
- Utilized transgenic mice expressing the human α-Synuclein gene (SNCA) and rotenone treatment.
- Administered chronic Dextran sodium sulfate (DSS) to induce gut inflammation and activate asparagine endopeptidase (AEP).
- Performed fecal microbiota transplantation (FMT) and live Helicobacter hepaticus (H. hepaticus) administration in antibiotic-pretreated SNCA mice.
Main Results:
- H. hepaticus was abundant in gut microbiota of rotenone-treated SNCA mice and PD patients.
- H. hepaticus initiated α-Synuclein pathology and motor deficits in SNCA mice in an AEP-dependent manner.
- DSS treatment activated AEP, leading to α-Synuclein cleavage, aggregation, and promotion of gut and brain inflammation and motor defects.
Conclusions:
- H. hepaticus, enriched in PD gut microbiomes, plays a key role in initiating α-Synuclein pathologies and motor impairments.
- AEP activation by H. hepaticus is a critical mechanism linking gut dysbiosis to PD pathogenesis.
- Targeting H. hepaticus or AEP may offer novel therapeutic strategies for Parkinson's disease.
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