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Published on: June 26, 2018
P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of
Eugene Huh1, Jin Gyu Choi2, Yujin Choi3
1Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea; Neurobiota Research Center, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
Background:
Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain.
Methods:
We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro.
Findings:
The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells.
Interpretation:
Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis.
Funding:
This study was supported by a grant from the National Research Foundation of Korea.
Insights
Proteus mirabilis bacteria can cause gut alpha-synuclein aggregation, leading to neurodegeneration. The virulence factor HpmA is key in this process, potentially indicating brain diseases.
Area of Science:
- Microbiology
- Neuroscience
- Gut-Brain Axis Research
Background:
- Emerging research highlights the gut microbiome's role in aggregated alpha-synuclein (α-syn) within the intestine.
- The gut-brain axis is increasingly explored for its potential involvement in central nervous system degeneration.
- Proteus mirabilis (P. mirabilis), a bacterium, has been implicated in animal models of brain neurodegeneration.
Purpose of the Study:
- To investigate the hypothesis that P. mirabilis virulence factors aggregate intestinal α-synuclein.
- To determine if these factors can initiate dopaminergic neurodegeneration in the brain via the gut-brain axis.
Main Methods:
- Utilized vagotomized and antibiotic-treated male murine models to study P. mirabilis pathogenesis in brain neurodegeneration.
- Employed genetically mutated P. mirabilis strains to identify specific neurodegenerative factors.
- Conducted in vitro experiments to analyze the pathological functions and interactions of virulence factors.
Main Results:
- P. mirabilis-induced motor dysfunction and neurodegeneration were linked to intestinal α-syn aggregation in treated murine models.
- Identified the virulence factor haemolysin A (HpmA) as crucial in P. mirabilis pathogenesis.
- Demonstrated HpmA's role in α-synuclein oligomerization and membrane pore formation, activating mTOR-mediated autophagy in intestinal neuroendocrine cells.
Conclusions:
- P. mirabilis-derived HpmA interacts with α-synuclein.
- HpmA may serve as a potential indicator for P. mirabilis-induced brain neurodegenerative diseases.
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