Involvement of Abnormal p-α-syn Accumulation and TLR2-Mediated Inflammation of Schwann Cells in Enteric Autonomic Nerve Dysfunction of Parkinson's Disease: an Animal Model Study.

Abstract

The study was designed to investigate the pathogenesis of gastrointestinal (GI) impairment in Parkinson's disease (PD). We utilized 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20mg/kg) and probenecid (250mg/kg) to prepare a PD mice model. MPTP modeling was first confirmed. GI motility was measured using stool collection test and enteric plexus loss was also detected. Intestinal phosphorylated α-synuclein (p-α-syn), inflammation, and S100 were assessed using western blotting. Association between Toll-like receptor 2(TLR2) and GI function was validated by Pearson's correlations. Immunofluorescence was applied to show co-localizations of intestinal p-α-syn, inflammation, and Schwann cells (SCs). CU-CPT22 (3mg/kg, a TLR1/TLR2 inhibitor) was adopted then. Success in modeling, damaged GI neuron and function, and activated intestinal p-α-syn, inflammation, and SCs responses were observed in MPTP group, with TLR2 related to GI damage. Increased p-α-syn and inflammatory factors were shown in SCs of myenteron for MPTP mice. Recovered fecal water content and depression of inflammation, p-α-syn deposition, and SCs activity were noticed after TLR2 suppression. The study investigates a novel mechanism of PD GI autonomic dysfunction, demonstrating that p-α-syn accumulation and TLR2 signaling of SCs were involved in disrupted gut homeostasis and treatments targeting TLR2-mediated pathway might be a possible therapy for PD.