Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration

The abnormal aggregation of a small number of known proteins underlies the most common human neurodegenerative diseases. In tauopathies and synucleinopathies, the normally soluble intracellular proteins tau and alpha-synuclein become insoluble and filamentous. In recent years, non-cell autonomous mechanisms of aggregate formation have come to the fore, suggesting that nucleation-dependent aggregation may occur in a localized fashion in human tauopathies and synucleinopathies, followed by seed-dependent propagation. There is a long prodromal phase between the formation of protein aggregates and the appearance of the first clinical symptoms, which manifest only after extensive propagation, opening novel therapeutic avenues. In tauopathies and synucleinopathies, the normally soluble intracellular proteins tau and alpha-synuclein become insoluble and filamentous. Goedert et al. review recent evidence for non-cell autonomous mechanisms of aggregate formation in these disorders. Increasing data suggest that nucleation-dependent aggregation occurs in a localised fashion, and is followed by seed-dependent propagation.