Objective: To investigate the modulatory effects of bacterial-derived proteins on the pathological aggregation of α-synuclein (α-syn)

Background: Aggregation of α-syn into toxic oligomers and protofibrils is a central pathogenic mechanism in Parkinson’s disease (PD). While proteolytic cleavage by human proteases generates fragments with distinct roles, the impact of microbial proteases on this prionoid protein remains unexplored.

Method: Escherichia coli-derived curli assembly protein (CsgC) and Cutibacterium acnes-derived serine protease 3 (CSPS3) were synthesized de novo. Aggregation kinetics of 10 μM human recombinant α-syn (± CSPS3/CsgC) were evaluated using a thioflavin-T (ThT) fluorescence assay over 360 minutes at 37°C. Conformational changes were assessed via a Congo red (CR) spectroscopic assay (absorbance 400–650 nm). Morphological characterization utilized transmission electron microscopy (TEM) with uranyl acetate negative staining at 120 kV.

Results: CSPS3 caused a dose-dependent reduction in the ThT fluorescence signal of α-syn. This was supported by the CR assay, showing a distinct shift in the absorption maximum from 510 nm in the presence of CSPS3. TEM imaging revealed that CSPS3-treated α-syn samples formed fewer and smaller aggregates versus untreated controls. Furthermore, CsgC inhibited α-syn aggregation but not amyloid-beta 42 (Aβ42) fibrillation, indicating client-specific selectivity.

Conclusion: The bacterial serine protease CSPS3 and curli assembly protein CsgC effectively inhibit in vitro α-syn fibrillation. This provides the first evidence that microbial proteins can modify the α-syn pathological aggregation process. These findings support investigating bacterial-derived proteins as potential PD therapeutic candidates.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/modulatory-effects-of-bacterial-derived-serine-protease-on-pathological-%ce%b1-synuclein-fibrillation-in-vitro/