α‑Synuclein Penetrates Mucin Hydrogels Despite Its Mucoadhesive Properties

• Published in: Biomacromolecules 2019-12, Vol.20 (12), p.4332-4344
• Main Authors: Marczynski, Matthias, Rickert, Carolin A, Semerdzhiev, Slav A, van Dijk, Wouter R, Segers-Nolten, Ine M. J, Claessens, Mireille M. A. E, Lieleg, Oliver
• Format: Article
• Language: English
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/acs.biomac.9b00905

Recent research indicates that the progression of Parkinson’s disease can start from neurons of the enteric nervous system, which are in close contact with the gastrointestinal epithelium: α-synuclein molecules can be transferred from these epithelial cells in a prion-like fashion to enteric neurons. Thin mucus layers constitute a defense line against the exposure of noninfected cells to potentially harmful α-synuclein species. We show thatdespite its mucoadhesive propertiesα-synuclein can translocate across mucin hydrogels, and this process is accompanied by structural rearrangements of the mucin molecules within the gel. Penetration experiments with different α-synuclein variants and synthetic peptides suggest that two binding sites on α-synuclein are required to accomplish this rearrangement of the mucin matrix. Our results support the notion that the translocation of α-synuclein across mucus barriers observed here might be a critical step in the infection of the gastrointestinal epithelium and the development of Parkinson’s disease.