Abstract
SummaryRecent discoveries have implicated the gut microbiome in the progression and severity of Parkinson’s disease; however, how gut bacteria affect such neurodegenerative disorders remains unclear. Here, we report that the Bacillus subtilis probiotic strain PXN21 inhibits α-synuclein aggregation and clears preformed aggregates in an established Caenorhabditis elegans model of synucleinopathy. This protection is seen in young and aging animals and is partly mediated by DAF-16. Multiple B. subtilis strains trigger the protective effect via both spores and vegetative cells, partly due to a biofilm formation in the gut of the worms and the release of bacterial metabolites. We identify several host metabolic pathways differentially regulated in response to probiotic exposure, including sphingolipid metabolism. We further demonstrate functional roles of the sphingolipid metabolism genes lagr-1, asm-3, and sptl-3 in the anti-aggregation effect. Our findings provide a basis for exploring the disease-modifying potential of B. subtilis as a dietary supplement.
Highlights
Protein misfolding and aggregation are key pathological features observed in numerous neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease (PD) (Ross and Poirier, 2004)
From analysis of gene expression profiles, we find that the protective effect of B. subtilis against a-syn aggregation is mediated through alterations in the sphingolipid metabolism pathway
B. subtilis Inhibits and Reverses a-Syn Aggregation in a C. elegans Model of Synucleinopathy To assess the effect of gut bacteria on a-syn aggregation, we used an established C. elegans model, expressing human a-syn fused to yellow fluorescent protein (YFP) and driven by a muscle-specific promoter (Punc-54::a-syn::YFP)
Summary
Protein misfolding and aggregation are key pathological features observed in numerous neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease (PD) (Ross and Poirier, 2004). PD is one of the most prevalent neurodegenerative disorders (Pringsheim et al, 2014) and is currently incurable. It is characterized by the progressive loss of dopaminergic neurons in the Substantia Nigra area of the brain, leading to the development of progressive motor and non-motor symptoms (Poewe et al, 2017). A-syn acquires neurotoxic properties when protein monomers progressively combine to form insoluble amyloid fibrils via oligomeric intermediates (Poewe et al, 2017). Lewy bodies contain mostly fibrillar forms of a-syn, oligomeric intermediates are toxic and play a central role in PD pathogenesis (Winner et al, 2011). Therapeutic strategies directed at inhibiting or reversing a-syn aggregation present a clear opportunity for disease-modifying interventions for PD and other synucleinopathies
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