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

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, 20 mg/kg) and probenecid (250 mg/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 (3 mg/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.

 

Comments:

The aim of the study was to examine the underlying causes of gastrointestinal (GI) dysfunction in Parkinson's disease (PD). To achieve this, the researchers used a mouse model of PD by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose of 20 mg/kg, along with probenecid at 250 mg/kg. The effectiveness of the MPTP model was confirmed, and GI motility was assessed using a stool collection test. Additionally, the loss of enteric plexus, a network of nerves within the intestines, was detected.

The study also investigated the presence of phosphorylated α-synuclein (p-α-syn), inflammation, and S100 in the intestines using western blotting. The researchers examined the association between Toll-like receptor 2 (TLR2) and GI function through Pearson's correlations. Immunofluorescence techniques were employed to visualize the co-localization of p-α-syn, inflammation, and Schwann cells (SCs) in the intestines. To further investigate the role of TLR2, the researchers used CU-CPT22, a TLR1/TLR2 inhibitor, at a dose of 3 mg/kg.

The study findings revealed successful modeling of PD, as evidenced by damaged GI neurons and impaired GI function. The researchers observed increased levels of intestinal p-α-syn, inflammation, and activated SC responses in the MPTP group. TLR2 was found to be associated with GI damage. The study also demonstrated elevated p-α-syn and inflammatory factors in SCs of the myenteron in MPTP mice. After TLR2 suppression using CU-CPT22, improvements in fecal water content and a reduction in inflammation, p-α-syn deposition, and SC activity were observed.

In conclusion, this study sheds light on a novel mechanism of autonomic dysfunction in the GI tract of PD. The accumulation of p-α-syn and TLR2 signaling in SCs were implicated in disrupted gut homeostasis. The findings suggest that therapies targeting the TLR2-mediated pathway may hold promise as a potential treatment for GI symptoms in PD.