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

Area of Science:

• Neuroscience
• Gastroenterology
• Cell Biology

Background:

• Emerging evidence suggests Parkinson's disease (PD) may originate in the enteric nervous system (ENS), a gut-innervated network.
• Most in vitro Parkinson's disease research focuses on the central nervous system, neglecting the ENS's role.
• The gut microbiome's influence on PD pathogenesis is increasingly recognized.

Purpose of the Study:

• To investigate the effects of preformed fibrils (PFFs) in a model of the enteric nervous system (ENS).
• To assess the impact of gut microbiome components (butyrate and lipopolysaccharide) on PFFs within the ENS.
• To evaluate functional and morphological changes in enteric neurons exposed to PFFs.

Main Methods:

• Utilized a preformed fibril (PFF) Parkinson's disease model.
• Co-administered butyrate and lipopolysaccharide to mimic gut microbiome effects.
• Isolated rat enteric neurons and cortical neurons were treated with PFFs.
• Assessed alpha-synuclein (a-Syn) aggregation via immunostaining.
• Analyzed neuronal growth cone morphology and dynamics.
• Performed electrophysiological recordings using microelectrode arrays (MEAs).
• Measured substance P levels.

Main Results:

• Enteric neurons showed significant uptake and retention of PFFs, with increased alpha-synuclein (a-Syn) aggregation.
• Cortical neurons also retained PFFs and exhibited increased a-Syn aggregation.
• PFF-treated ENS cultures displayed altered growth cone morphology but not dynamics.
• No significant changes in spontaneous neuronal firing rate were detected via MEA.
• Untreated controls responded to dopamine stimulus, while PFF-treated neurons responded to acetylcholine.
• Substance P levels remained unchanged, indicating no direct correlation with PD or neurodegeneration in this model.

Conclusions:

• The enteric nervous system (ENS) can retain Parkinson's disease-associated preformed fibrils (PFFs) without acute functional decline.
• Exposure to PFFs induces changes in neuronal growth cone morphology and alters dopamine-stimulated activity in the ENS.
• These findings highlight the ENS's susceptibility to PFFs and suggest a potential role in Parkinson's disease pathogenesis.
• The study provides insights into gut-brain axis mechanisms relevant to Parkinson's disease.