Thermal proteome profiling unveils protein targets of deoxycholic acid in living neuronal cells

Abstract Bile acids, synthesized in the liver and modified by the gut microbiota, play vital roles in various physiological processes. The dysregulation of bile acids has been extensively documented in patients with neurodegenerative diseases. However, limited attention has been given to the protein targets associated with microbiota-derived bile acids in neurological diseases. To address this knowledge gap, we conducted comprehensive thermal proteomic analyses to elucidate and comprehend the protein targets affected by microbiota-derived bile acids. Our investigation identified sixty-five unique proteins in SH-SY5Y neuronal cells as potential targets of deoxycholic acid (DCA), a primary component of the bile acid pool originating from the gut microbiota. Notably, Nicastrin and Casein kinase 1 epsilon stood out among these proteins. We found that DCA, through its interaction with the Nicastrin subunit of γ-secretase, significantly contributed to the formation of amyloid beta, a key hallmark in the pathology of neurodegenerative diseases. In summary, our findings provide crucial insights into the intricate interplay between microbiota-derived bile acids and the pathogenesis of neurodegenerative diseases, thereby shedding light on potential therapeutic targets for neurodegenerative diseases.