Multiomic Analysis Reveals Molecular Pathways Associated with Intestinal Aggregation of α-Synuclein

Area of Science:

• Neuroscience
• Gastroenterology
• Biochemistry

Background:

• Parkinson's disease (PD) is linked to alpha-synuclein aggregation, potentially originating in the gut.
• Enteroendocrine cells in the gut express alpha-synuclein and interact with the nervous system.
• Gut microbiota metabolites, like nitrite, can induce alpha-synuclein aggregation in these cells.

Purpose of the Study:

• To elucidate the cellular and molecular mechanisms of nitrite-induced alpha-synuclein aggregation in enteroendocrine cells.
• To investigate the role of dopamine in this aggregation process.
• To explore potential therapeutic strategies targeting gut-initiated PD.

Main Methods:

• Untargeted proteomics of nitrite-exposed enteroendocrine cells.
• Targeted analysis of dopamine's role in alpha-synuclein aggregation.
• Lipidome profiling of enteroendocrine cells.
• Assessment of cell viability under stress conditions.

Main Results:

• Nitrite exposure initiates alpha-synuclein aggregation in enteroendocrine cells via specific pathways.
• Dopamine is critical for nitrite-induced aggregation; its absence suppresses aggregation.
• Enteroendocrine cells exhibit robustness, potentially serving as reservoirs for aggregates.
• Inhibitors of dopamine biosynthesis (benserazide, alpha-methyl tyrosine) reduced aggregation.

Conclusions:

• Enteroendocrine cells are key players in the gut-initiated cascade of Parkinson's disease.
• Dopamine metabolism is a critical target for preventing alpha-synuclein aggregation in the gut.
• Further research into lipid metabolism in PD is warranted.
• These findings support the development of therapies to prevent gut-to-brain alpha-synuclein spread.