Disintegration of amyloid fibrils of alpha-synuclein by dequalinium.
alpha-Synuclein is the major amyloidogenic component observed in the Lewy bodies of Parkinson's disease. Amyloid fibrils of alpha-synuclein prepared in vitro were instantaneously disintegrated by dequalinium (DQ). Double-headed cationic amphipathic structure of DQ with two aminoquinaldinium rings at both ends turned out to be crucial to exert the disintegration activity. The defibrillation activity was shown to be selective toward the fibrils of alpha-synuclein and Abeta40 while the other beta2-microglobulin amyloid fibrils were not susceptible so much. Besides the common cross beta-sheet conformation of amyloid fibrils, therefore, additional specific molecular interactions with the target amyloidogenic proteins have been expected to be involved for DQ to exhibit its defibrillation activity. The disintegrating activity of DQ was also evaluated in vivo with the yeast system overexpressing alpha-synuclein-GFP. With the DQ treatment, the intracellular green inclusions turned into green smears, which resulted in the enhanced cell death. Based on the data, the previous observation that DQ led to the predominant protofibril formation of alpha-synuclein could be explained by the dual function of DQ showing both the facilitated self-oligomerization of alpha-synuclein and the instantaneous defibrillation of its amyloid fibrils. In addition, amyloidosis-related cytotoxicity has been demonstrated to be amplified by the fragmentation of mature amyloid fibrils by DQ.
Park
Jae-Woo
JW
School of Chemical and Biological Engineering, College of Engineering, Seoul National University, Gwanak-Ku, Seoul 151-744, South Korea.
Lee
In-Hwan
IH
Hahn
Ji-Sook
JS
Kim
Jongsun
J
Chung
Kwang Chul
KC
Paik
Seung R
SR
D000682:Amyloid / Q000378:metabolism*; D003868:Dequalinium / Q000737:chemistry / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism*
D000682:Amyloid; D003902:Detergents; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D003868:Dequalinium