Clustering of human prion protein and α-synuclein oligomers requires the prion protein N-terminus

The interaction of prion protein (PrP) and alpha -synuclein (alpha Syn) oligomers causes synaptic impairment that might trigger Parkinson's disease and other synucleinopathies. Here, we report that alpha Syn oligomers (alpha SynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of alpha Syn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric alpha Syn. The stoichiometry of the heteroassemblies is well defined with an alpha Syn:huPrP molar ratio of about 1:1. The alpha SynO-huPrP interaction is of high affinity, signified by slow dissociation. The huPrP region responsible for condensation of alpha SynO, residues 95-111 in the intrinsically disordered N-terminus, corresponds to the region required for alpha SynO-mediated cognitive impairment. HuPrP, moreover, achieves co-clustering of alpha SynO and Alzheimer's disease-associated amyloid-beta oligomers, providing a case of a cross-interaction of two amyloidogenic proteins through an interlinking intrinsically disordered protein region. The results suggest that alpha SynO-mediated condensation of huPrP is involved in the pathogenesis of synucleinopathies. Nadine S. Rosener et al. show that alpha -synuclein oligomers can cluster with human prion protein (huPrP) into condensates. The intrinsically disordered N-terminus of huPrP is necessary for this high-affinity interaction, suggesting a link between cluster formation and toxicity.