Data for: Multiomic analysis reveals molecular pathways associated with intestinal aggregation of α-synuclein

Here, we detail the cellular and molecular mechanisms involved. First, we holistically profiled nitrite-exposed enteroendocrine cells through untargeted proteomics. Next, we performed targeted analyses that specifically probed the mechanistic role of dopamine, as our prior findings suggested that dopamine is critical for nitrite-induced α-synuclein aggregation.

In dopamine-free HeLa cells treated with nitrite, α-synuclein aggregation was indeed suppressed. Proteomic signatures in dopamine-free cells treated with nitrite were distinct from those in nitrite-treated enteroendocrine cells, highlighting pathways relevant to intestinal development of PD. Intriguingly, we observed that enteroendocrine cells maintain viability upon exposure to nitrite and in the presence of α-synuclein aggregates.

This cellular robustness suggests that these cells may be a reservoir of toxic α-synuclein aggregates. As a possible antidote, our findings show that benserazide and α-methyl tyrosine, chemical inhibitors of dopamine biosynthesis, limited aggregation. Curious about mechanisms of disease etiology outside of α-synuclein aggregation, we also profiled the enteroendocrine cell lipidome, an emerging area of interest in PD research, to motivate future targeted studies delineating the roles of dysregulated lipid metabolism in disease onset.

Overall, these studies lay a foundation for mechanistically informed therapeutic targets to prevent the intestinal formation of α-synuclein aggregates before they spread to the brain.