α-synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells

Hurley, M. J.; Menozzi, E.; Koletsi, S.; Bates, R.; Gegg, M. E.; Chau, K.-Y.; Blottiere, H. M.; Macnaughtan, J.; Schapira, A. H. V.

doi:10.1101/2023.04.02.535274

bioRxiv · 10.1101/2023.04.02.535274

α-synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells

Hurley, M. J.·Menozzi, E.·Koletsi, S.·Bates, R.·Gegg, M. E.·Chau, K.-Y.·Blottiere, H. M.·Macnaughtan, J.·Schapira, A. H. V.

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Abstract

BackgroundCaudo-rostral migration of pathological forms of -synuclein from the gut to the brain is proposed as an early feature in Parkinson disease (PD) pathogenesis, but the underlying mechanisms remain unknown. Intestinal enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in PD patients and these alterations can trigger -synuclein pathology in animal models. ObjectiveHere we investigated the effect of toll-like receptor (TLR) and free fatty acid receptor (FFA2/3) agonists on -synuclein levels in mouse STC-1 enteroendocrine cells. MethodsSTC-1 cells were treated with TLR and FFA2/3 agonists alone and in combination with selective antagonists. The level of -synuclein protein was measured in cell lysates and cell culture media by western blot and ELISA. And the level of -synuclein and tumour necrosis factor (TNF) mRNA was measured by quantitative RT-PCR. ResultsTLR and FFA receptor agonists significantly increased intracellular and extracellular -synuclein levels and antagonists significantly reduced these effects. TLR and FFA receptor agonists also significantly increased TNF transcription and this was inhibited by corresponding antagonists. ConclusionsElevated intracellular -synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce -synuclein accumulation in STC-1 cells. Here we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in PD gut dysbiosis might facilitate accumulation and transmission of -synuclein pathology from the gut to the brain.

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Hurley, M. J., Menozzi, E., Koletsi, S., Bates, R., Gegg, M. E., Chau, K.-Y., Blottiere, H. M., Macnaughtan, J., Schapira, A. H. V.. 2023-04-02. α-synuclein expression in response to bacterial ligands and metabolites in gut enteroendocrine cells. https://doi.org/10.1101/2023.04.02.535274

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