Forcing nonamyloidogenic β-synuclein to fibrillate

Ghiam Yamin, Larissa A. Munishkina, Mikhail A. Karymov, Yuri L. Lyubchenko, Vladimir N. Uversky, Anthony L. Fink

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90 Scopus citations

Abstract

The fibrillation and aggregation of α-synuclein is a key process in the formation of intracellular inclusions, Lewy bodies, in substantia nigral neurons and, potentially, in the pathology of Parkinson's disease and several other neurodegenerative disorders. α-Synuclein and its homologue β-synuclein are both natively unfolded proteins that colocalize in presynaptic terminals of neurons in many regions of the brain, including those of dopamine-producing cells of the substantia nigra. Unlike its homologue, β-synuclein does not form fibrils and has been shown to inhibit the fibrillation of α-synuclein. In this study, we demonstrate that fast and efficient aggregation and fibrillation of β-synuclein can be induced in the presence of a variety of factors. Certain metals (Zn2+, Pb 2+, and Cu2+) induce a partially folded conformation of β-synuclein that triggers rapid fibrillation. In the presence of these metals, mixtures of α- and β-synucleins exhibited rapid fibrillation. The metal-induced fibrillation of β-synuclein was further accelerated by the addition of glycosaminoglycans or high concentrations of macromolecular crowding agents. β-Synuclein also rapidly formed soluble oligomers and fibrils in the presence of pesticides, whereas the addition of low concentrations of organic solvents induced formation of amorphous aggregates. These new findings demonstrate the potential effect of environmental pollutants in generating an amyloidogenic, and potentially neurotoxic, conformation, in an otherwise benign protein.

Original languageEnglish (US)
Pages (from-to)9096-9107
Number of pages12
JournalBiochemistry
Volume44
Issue number25
DOIs
StatePublished - Jun 28 2005

ASJC Scopus subject areas

  • Biochemistry

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    Yamin, G., Munishkina, L. A., Karymov, M. A., Lyubchenko, Y. L., Uversky, V. N., & Fink, A. L. (2005). Forcing nonamyloidogenic β-synuclein to fibrillate. Biochemistry, 44(25), 9096-9107. https://doi.org/10.1021/bi048778a