Silk fibroin as a modulator of the amyloidogenic α-synuclein aggregation

The aggregation of fiber-forming proteins presents a duality of biological functions, where certain proteins, such as α-synuclein, are implicated in neurodegenerative disorders like Parkinson’s, while others, like silk fibroin, serve as essential building blocks for functional biomaterials. Despite ongoing investigations into the interplay between these contrasting protein groups, existing reports suggest that the presence of “functional” fibrillar proteins can accelerate amyloid growth via a crowding effect. In this study, we report a counterintuitive outcome, demonstrating that silk fibroin inhibits amyloidogenic aggregation of α-synuclein protein. Our findings reveal that although the fibrillar aggregation of both proteins—individually and in mixtures—remains affected by environmental factors such as concentration and temperature, silk fibroin significantly alters the rheological behavior of the mixed solutions. Our structural and kinetic analyses reveal that silk modifies the structural transitions and self-assembly dynamics of α-synuclein through macromolecular crowding and non-specific interactions that eventually suppressed the amyloidogenic aggregation of the α-synuclein. Notably, when nanofibrillar amyloidogenic assemblies are forced to form in the presence of silk, they exhibit a markedly increased susceptibility to enzymatic degradation, a phenomenon not observed with pure α-synuclein fibrillar constructs. These results prompt further investigation into the potential role of “functional” fiber-forming proteins in modulating protein aggregation processes and their implications for therapeutic strategies against neurodegenerative diseases.