Beschreibung
The accumulation of misfolded alpha-synuclein (αSyn) protein into pathological aggregates plays a central role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies. Although PD is primarily considered a central nervous system disease, multiple studies have implicated the gut microbiome in its progression and severity. However, how gut bacteria affect PD remains unclear. We have previously shown that B. subtilis PXN21, a probiotic strain commercially available, extends lifespan, inhibits αSyn inclusions, and efficiently removes preformed inclusions in a C. elegans model with ectopic expression of human αSyn (Goya et al, 2020). This protection is partly mediated by DAF-16 (FOXO) and changes in the sphingolipid metabolism in the host. To uncover protective bacterial metabolic pathways, we screened a genome-wide B. subtilis single-gene deletion library of non-essential genes (Koo et al, 2017). Genes involved in the TCA cycle, ATP synthesis, and purine metabolism from B. subtilis are involved in modulating αSyn inclusions in the host. Given that purine metabolism is deregulated in PD at transcriptomic and metabolic levels, but its relevance is not fully understood yet, we decided to focus on this pathway. Among the top hits, we identified B. subtilis delta purB, encoding for adenylosuccinate lyase, an enzyme involved in two steps within the purine biosynthesis. By genetic and pharmacological complementation assays, we are dissecting the role of specific metabolites from the purine metabolism on αSyn inclusions and their toxicity in the worm. Overall, our study has the potential to reveal microbiome-host genetic interactions with disease-modifying potential for PD.
| Affiliation | European Institute for the Biology of Aging (ERIBA), University of Groningen (UMCG), The Netherlands |
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