α-Synuclein Penetrates Mucin Hydrogels Despite Its Mucoadhesive Properties

Abstract

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.

Repulsive Backbone–Backbone Interactions Modulate Access to Specific and Unspecific Binding Sites on Surface-Bound Mucins

“…For interpreting the binding results presented here, using surface-bound mucins helps us avoiding certain technical complications: for instance, as dextran molecules carry multiple charges (∼5 charges for the 4 kDa dextrans and ∼185 charges for the 150 kDa dextrans), the polyanionic/polycationic character of those macromolecules could lead to intermolecular interactions of mucin molecules with each other (e.g., triggered via crosslinking by the dextrans) and thus to the formation of agglomerates. 50 Possible Physiological Role of MUC5AC-Associated DNA. We here study porcine gastric MUC5AC, which we purify manually in the lab.…”

Reduced acetylcholine and elevated muscarinic receptor 2 in duodenal mucosa contribute to the impairment of mucus secretion in 6-hydroxydopamine-induced Parkinson’s disease rats

“…After 15 min of equilibration, the duodenal preparations were routinely treated with a cyclooxygenase inhibitor, indomethacin (10 μM; Sigma, I8280), and a neuronal Na + channel blocker, tetrodotoxin (TTX, 1 μM; Kangte Biological Engineering Co., Ltd, Xinghua, Jiangsu, China), to abolish the effects of endogenous prostaglandin and the remnant enteric nervous system (ENS). All segments were incubated with or without carbachol (CCh) (Tocris; 2810), pirenzepine (Sigma; P7412), methoctramine (Sigma; M105), and 4-DAMP (Sigma; SML0255) for 30 min at 37 °C, which is comparable to the physiological mucus turnover time (Marczynski et al 2019). The supernatants were collected to detect the MUC2 content, which was determined by ELISA according to the manufacturer's instructions (Cloud-Clone Corp, SEA705Ra, Wuhan, China).…”

Molecular Communication Between Neuronal Networks and Intestinal Epithelial Cells in Gut Inflammation and Parkinson's Disease

“…In order to get in contact with IECs, aSyn should translocate across the mucus barrier protecting the monolayer of epithelial cells. A recent study has shown that, despite mucoadhesive properties, aSyn penetrates the mucus by inducing rearrangement of the mucin matrix (246). Other studies suggest that rather than aSyn itself, other phenomena associated with alterations of the microbiota, such as increased levels of LPS are responsible for epithelial alterations, including redistribution of ZO1 and E-cadherin (244).…”