Soluble N-Terminal Domain of the Prion Protein Interferes with Fibrillization of α-Synuclein to Form Off-Pathway Assemblies that Lack Cellular Seeding Activity

Abstract

Disease progression in synucleinopathies is associated with the formation of seeding-competent α-synuclein (αSyn) aggregates. After spreading and cellular uptake, the αSyn seeds propagate in a prion-like mechanism by inducing the conversion of natively folded αSyn into pathogenic aggregates. Here we show that the soluble intrinsically disordered N-terminal domain of the cellular prion protein (N1-PrP) modulates fibrillization of αSyn to form off-pathway aggregates that lack seeding activity in cells. N1-PrP does not interact with soluble αSyn. However, during the aggregation of αSyn in vitro, N1-PrP is recruited and incorporated. As a result, amorphous coaggregates are formed instead of seeding-competent αSyn fibrils. Similarly, in the cytosol of neuronal cells N-PrP specifically interacts with αSyn during the prion-like propagation of pathogenic αSyn seeds. These findings identify a unique neuroprotective activity of the soluble N-terminal domain of the prion protein by promoting off-pathway reactions in amyloid seed formation.