P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration

Background Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (alpha-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 alpha-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 alpha-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 alpha-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 alpha-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.Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study explores the role of the gut microbiome and the gut-brain axis in central nervous system degeneration. It finds that Proteus mirabilis can induce the aggregation of intestinal alpha-synuclein, resulting in dopaminergic neurodegeneration in the brain. The specific virulence factor haemolysin A is involved in this process by activating the autophagy signaling pathway in intestinal neuroendocrine cells.