Alpha-Synuclein

Abstract

α-Synuclein (αS) is the major component of Lewy bodies in Parkinson’s disease and dementia with Lewy bodies, and glial cytoplasmic inclusions in multiple system atrophy. Immunocytochemical studies revealed widespread abnormal αS pathologies in these diseases, and the prion-like spreading of the αS pathologies has been proposed. To elucidate the prion-like properties of abnormal αS in vitro, in cells, and in animal experimental models, we prepared several kinds of αS aggregates or intermediates under various conditions and examined their seeding ability. The conversion of soluble αS into amyloid-like fibrils was accelerated by addition of small amounts of preformed αS fibrils, and the acceleration was increased in proportion to the sonication time of the fibrils, suggesting that fragmentation of the fibrils is important for the prion-like conversion. In cultured cells, introduction of fragmented αS fibrils also promoted seed-dependent aggregation, and αS fibrils with less than 50 nm in size were the most efficient for prion-like propagation in mice. Furthermore, injection of the αS fibrils into wild-type marmoset brains resulted in spreading of abundant αS pathologies. Robust Lewy body-like inclusions were formed in TH-positive neurons, strongly suggesting the retrograde spreading of abnormal αS. Moreover, a significant decrease in the numbers of TH-neurons was observed. Furthermore, most of the αS inclusions were positive for beta-sheet ligands such as thioflavin-S. These results demonstrate that fragmented αS fibrils are the key pathogenic seeds that trigger prion-like conversion.