Pathogenic mechanisms of prion protein, amyloid-β and α-synuclein misfolding: the prion concept and neurotoxicity of protein oligomers

Proteinopathies represent a group of diseases characterized by the unregulated misfolding and aggregation of proteins. Accumulation of misfolded protein in the central nervous system (CNS) is associated with neurodegenerative diseases, such as the transmissible spongiform encephalopathies (or prion diseases), Alzheimer's disease, and the synucleinopathies (the most common of which is Parkinson's disease). Of these, the pathogenic mechanisms of prion diseases are particularly striking where the transmissible, causative agent of disease is the prion, or proteinaceous infectious particle. Prions are composed almost exclusively of PrPSc; a misfolded isoform of the normal cellular protein, PrPC, which is found accumulated in the CNS in disease. Today, mounting evidence suggests other aggregating proteins, such as amyloid-beta (Ab) and alpha-synuclein (alpha-syn), proteins associated with Alzheimer's disease and synucleinopathies, respectively, share similar biophysical and biochemical properties with PrPSc that influences how they misfold, aggregate, and propagate in disease. In this regard, the definition of a 'prion' may ultimately expand to include other pathogenic proteins. Unifying knowledge of folded proteins may also reveal common mechanisms associated with other features of disease that are less understood, such as neurotoxicity. This review discusses the common features A beta and alpha-syn share with PrP and neurotoxic mechanisms associated with these misfolded proteins.