Neurodegenerative disorders are associated with intra- or extra-cellular deposition of aggregates of misfolded insoluble proteins. These deposits composed of tau, amyloid-β or α-synuclein spread from cell to cell, in a prion-like manner. Novel evidence suggests that the circulating soluble oligomeric species of these misfolded proteins could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Recent convincing data support the proposition that the cellular prion protein, PrP^C, act as a toxicity-inducing receptor for amyloid-β oligomers. As a consequence, several studies focused their investigations to the role played by PrP^C in binding other protein aggregates, such as tau and α-synuclein, for its possible common role in mediating toxic signalling. The biological relevance of PrP^C as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrP^Sc included, could lead to relevant therapeutic implications. Here we describe the structure of PrP^C and the proposed interplay with its pathological counterpart PrP^Sc and then we recapitulate the most recent findings regarding the role of PrP^C in the interaction with aggregated forms of other neurodegeneration-associated proteins.