Discovery of a Gut Bacterial Metabolic Pathway that Drives α-Synuclein Aggregation and Neurodegeneration

Abstract

AbstractParkinson’s disease (PD) etiology is associated with aggregation and accumulation of α-synuclein (α- syn) proteins in midbrain dopaminergic neurons. Emerging evidence suggests that in certain subtypes of PD, α-syn aggregates originate in the gut and subsequently spread to the brain. However, the mechanisms that instigate α-syn aggregation in the gut have remained elusive. In the brain, the aggregation of α-syn is induced by oxidized dopamine. Such a mechanism has not been explored in the gastrointestinal (GI) tract, a niche harboring 46% of the body’s dopamine reservoirs. Here, we report that gut bacteria Enterobacteriaceae induce α-syn aggregation. More specifically, our in vitro data indicate that respiration of nitrate by Escherichia coli K-12 yields nitrite, a potent oxidizing agent that creates an oxidizing redox potential in the bacterial environment. In these conditions, Fe2+ was oxidized to Fe3+, enabling formation of dopamine-derived quinones and α-syn aggregates. Exposing nitrite, but not nitrate, to enteroendocrine STC-1 cells induced aggregation of α-syn that is natively expressed in these cells, which line the intestinal tract. Finally, we examined the in vivo relevance of bacterial nitrate respiration to the formation of α-syn aggregates using Caenorhabditis elegans models of PD. We discovered that nematodes exposed to nitrate-reducing E. coli K-12 displayed significantly enhanced neurodegeneration as compared to an E. coli K-12 mutant that could not respire nitrate. This neurodegenerative effect was absent when α-syn was mutated to prevent interactions with dopamine-derived quinones. Taken together, our findings indicate that gut bacterial nitrate reduction may be critical to initiating intestinal α- syn aggregation.Table of Contents Graphic