Dequalinium-induced protofibril formation of α-synuclein

Choong Hwan Lee, Jin Kim Hyun, Jung Ho Lee, Hyun Ju Cho, Jongsun Kim, Chul Chung Kwang, Seunho Jung, Seung R. Paik

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Abstract

α-Synuclein is the major constituent of Lewy bodies, a pathological signature of Parkinson disease, found in the degenerating dopaminergic neurons of the substantia nigra pars compacta. Amyloidosis generating the insoluble fibrillar protein deposition has been considered to be responsible for the cell death observed in the neurodegenerative disorder. In order to develop a controlling strategy toward the amyloid formation, 1,1′-(1,10-decanediyl)- bis-[4-amino-2-methylquinolinium] (dequalinium), was selected and examined in terms of its specific molecular interaction with α-synuclein. The protein was self-oligomerized by dequalinium, which gave rise to the ladder formation on N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine/SDS-PAGE in the presence of a coupling reagent of N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. The double-headed structure of dequalinium with the two cationic 4-aminoquinaldinium rings was demonstrated to be critical for the protein self-oligomerization. The dequalinium-binding site was located on the acidic C-terminal region of the protein with an approximate dissociation constant of 5.5 μM. The protein self-oligomerization induced by the compound has resulted in the protofibril formation of α-synuclein before it has developed into amyloids. The protofibrils were demonstrated to affect the membrane intactness of liposomes, and they have also been shown to influence cell viability of human neuroblastoma cells. In addition, dequalinium treatment of the α-synuclein- overexpressing cells exerted a significant cell death. Therefore, it is pertinent to consider that dequalinium could be used as amolecular probe to assess toxic mechanisms related to the amyloid formation of α-synuclein. Ultimately, the compound could be employed to develop therapeutic and preventive strategies toward α-synucleinopathies including Parkinson disease.

Original languageEnglish
Pages (from-to)3463-3472
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number6
DOIs
Publication statusPublished - 2006 Feb 10

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lee, C. H., Hyun, J. K., Lee, J. H., Cho, H. J., Kim, J., Kwang, C. C., Jung, S., & Paik, S. R. (2006). Dequalinium-induced protofibril formation of α-synuclein. Journal of Biological Chemistry, 281(6), 3463-3472. https://doi.org/10.1074/jbc.M505307200