β-Synuclein Assembly as a Therapeutic Target of Parkinson's Disease and Related Disorders

Lewy bodies (LBs) and Lewy neurites (LNs) in the brain constitute the main histopathological features of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and are comprised of amyloid-like fibrils composed of a small protein (∼14 kDa) named alpha-synuclein (αS). As the aggregation of αS in the brain has been implicated as a critical step in the development of the diseases, the current search for disease-modifying drugs is focused on modification of the process of αS deposition in the brain. In this article, the recent developments on the molecules that inhibit the formation of α-synuclein fibrils (fαS) as well as the oligomerization of αS are reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation of fαS, and to destabilize preformed fαS at pH 7.5 at 37°C in vitro. Although the mechanisms by which these compounds inhibit fαS formation from fαS, and destabilize preformed fαS are still unclear, they could be key molecules for the development of preventives and therapeutics for PD and other α-synucleinopathies.