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Neurodegenerative disorders are invariably associated with intra- or extra-cellular deposition of aggregates composed of misfolded insoluble proteins. These deposits composed of tau, amyloid-β or α-synuclein spread from cell to cell, in a prion-like manner. Emerging evidence suggests that the circulating soluble species of these misfolded proteins (usually referred as oligomers) could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Convincing data support the hypothesis that the cellular prion protein, PrPC, act as a toxicity-transducing receptor for amyloid-β oligomers. As a consequence, several studies extended investigations to the role played by PrPC in binding aggregates of proteins other than Aβ, such as tau and α-synuclein, for its possible common role in mediating toxic signaling. A better characterization of the biological relevance of PrPC as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrPSc included, would bring relevant therapeutic implications. Here we will first describe the structure of the prion protein and the hypothesized interplay with its pathological counterpart PrPSc and then we will recapitulate the most relevant discoveries regarding the role of PrPC in the interaction with aggregated forms of other neurodegeneration-associated proteins.