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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

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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, 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.

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Data Availability

Data are available upon reasonable request.

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Acknowledgements

All of the authors are grateful to the members of Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology of Nanjing Medical University for the technical assistance.

Funding

The research was supported by National Natural Science Foundation of China (Grant No. 82071431).

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Author notes

  1. Wenwen Jiang, Yue Cheng, and Ye Wang contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Wenwen Jiang, Yue Cheng, Ye Wang, Zhe Rong & Kezhong Zhang

  2. Department of Neurology, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212000, China

    Jing Wu

  3. Department of Neurology, Suzhou Ninth People’s Hospital, Suzhou, 215200, China

    Li Sun

  4. Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China

    Yan Zhou

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Contributions

Conceptualization: W.J., Y.C., and Y.W.; experimentation: W.J., Y.C., Y.W., J.W., Z.R., L.S., and Y.Z.; writing—original draft: W.J., Y.C., and Y.W.; writing—review and editing: K.Z. and Y.Z.; funding acquisition: K.Z. All of the authors contributed in editing the manuscript and read and approved the publication of the submitted version.

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Correspondence to Yan Zhou or Kezhong Zhang.

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Jiang, W., Cheng, Y., Wang, Y. et al. 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. Mol Neurobiol 60, 4738–4752 (2023). https://doi.org/10.1007/s12035-023-03345-4

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