Synthetic Sulfated Polymers Control Amyloid Aggregation of Ovine Prion Protein and Decrease Its Toxicity

Amyloid aggregation, including aggregation and propagation of prion protein, is a key factor in numerous human diseases, so-called amyloidosis, with a very poor ability for treatment or prevention. The present work describes the effect of sulfated or sulfonated polymers (sodium dextran sulfate, polystyrene sulfonate, polyanethole sulfonate, and polyvinyl sulfate) on different stages of amyloidogenic conversion and aggregation of the prion protein, which is associated with prionopathies in humans and animals. All tested polymers turned out to induce amyloid conversion of the ovine prion protein. As suggested from molecular dynamics simulations, this effect probably arises from destabilization of the native prion protein structure by the polymers. Short polymers enhanced its further aggregation, whereas addition of high-molecular poly(styrene sulfonate) inhibited amyloid fibrils formation. According to the seeding experiments, the protein-polymer complexes formed after incubation with poly(styrene sulfonate) exhibited significantly lower amyloidogenic capacity compared with the control fibrils of the free prion protein. The cytotoxicity of soluble oligomers was completely inhibited by treatment with poly(styrene sulfonate). To summarize, sulfonated polymers are a promising platform for the formulation of a new class of anti-prion and anti-amyloidosis therapeutics.

Automated summary

The effect of sulfated or sulfonated polymers on amyloid conversion and aggregation of prion protein was investigated. The results showed that these polymers induce amyloid conversion of the prion protein, possibly by destabilizing its native structure. Short polymers enhanced further aggregation, while high-molecular poly(styrene sulfonate) inhibited amyloid fibrils formation. The protein-polymer complexes formed after incubation with poly(styrene sulfonate) had significantly lower amyloidogenic capacity and inhibited the cytotoxicity of soluble oligomers. This suggests that sulfonated polymers could be a promising platform for the development of anti-prion and anti-amyloidosis therapeutics.