The prion hypothesis of Parkinson's disease

The discovery of alpha-synuclein's prion-like behaviors in mammals, as well as a non-Mendelian type of inheritance, has led to a new concept in biology, the "prion hypothesis" of Parkinson's disease. The misfolding and aggregation of alpha-synuclein (α-syn) within the nervous system occur in many neurodegenerative diseases including Parkinson's disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). The molecular basis of synucleinopathies appears to be tightly coupled to α-syn's conformational conversion and fibril formation. The pathological form of α-syn consists of oligomers and fibrils with rich in β-sheets. The conversion of its α-helical structure to the β-sheet rich fibril is a defining pathologic feature of α-syn. These kinds of disorders have been classified as protein misfolding diseases or proteopathies which share key biophysical and biochemical characteristics with prion diseases. In this review, we highlight α-syn's prion-like activities in PD and PD models, describe the idea of a prion-like mechanism contributing to PD pathology, and discuss several key molecules that can modulate the α-syn accumulation and propagation.