Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro

Recent evidence implicates a gut-first pathogenesis in the enteric nervous system (ENS) within a portion of PD patients, yet in vitro investigations have primarily focused on the central nervous system. Here, the preformed fibril (PFF) PD model is applied with co-administered groups of butyrate and lipopolysaccharide to model the effects of the local gut microbiome. Significant PFF uptake and retention occur in isolated rat enteric neurons compared to untreated controls resulting in increasing immunostained aggregate conformation-specific, alpha-synuclein (a-Syn) average intensity between 6 mu g PFF and untreated controls. Cortical neurons significantly retain PFFs with an increase in aggregated a-Syn average intensity within all dosages. Differences in growth cone morphology but not dynamics in PFF-treated ENS cultures occur. Electrophysiological recordings via a microelectrode array (MEA) indicate no overall difference in spontaneous spike rate. However, only untreated controls respond to PD-relevant dopamine stimulus, while 1 mu g PFF and control populations respond to stimulus with ENS-abundant acetylcholine. Finally, no differences in substance P levels-correlated with PD and neurodegeneration-are observed. Overall, these findings suggest the ENS retains PFF dosage absent acute loss in function, however, does experience changes in growth cone morphology and dopamine-stimulated activity.

Automated summary

Recent research suggests that the enteric nervous system (ENS) in Parkinson's disease (PD) patients may play a role in the development of the disease. In this study, a preformed fibril (PFF) PD model was used, and the effects of the local gut microbiome were simulated by co-administering butyrate and lipopolysaccharide. The results showed that isolated rat enteric neurons took up and retained PFFs, leading to an increase in the intensity of aggregated alpha-synuclein (a-Syn) compared to untreated controls. The morphology of growth cones was affected by PFF treatment, but not their dynamics. While no overall difference in spontaneous spike rate was observed, only the untreated controls responded to a dopamine stimulus relevant to PD.