The Oligomer Hypothesis in α-Synucleinopathy

Lewy bodies and Lewy neurites in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies. They comprise amyloid-like fibrils composed of α-synuclein (αS), a small protein (~14 kDa). Because the aggregation of αS in the brain has been implicated as a critical step in the development of these diseases, the research for disease-modifying drugs has focused on modification of the αS aggregation process in the brain. Recent studies using synthetic αS peptides, a cell culture model, transgenic mice models, and human samples such as cerebrospinal fluids and the blood of PD patients have suggested that pre-fibrillar forms of αS (i.e., oligomers) are more critical than fibrillar forms (such as Lewy bodies) in the pathogenesis of α-synucleinopathies. Based on the accumulating evidence that oligomers play a central role in the pathogenesis of PD and other α-synucleinopathies (the "oligomer hypothesis"). This report reviews the recent findings regarding the oligomer hypothesis in the research of α-synucleinopathies.