Dynamics of α-synuclein aggregation and inhibition of pore-like oligomer development by β-synuclein

Igor F. Tsigelny, Pazit Bar-On, Yuriy Sharikov, Leslie Crews, Makoto Hashimoto, Mark A. Miller, Steve H. Keller, Oleksandr Platoshyn, Jason X.J. Yuan, Eliezer Masliah

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

Accumulation of α-synuclein resulting in the formation of oligomers and protofibrils has been linked to Parkinson's disease and Lewy body dementia. In contrast, β-synuclein (β-syn), a close homologue, does not aggregate and reduces α-synuclein (α-syn)-related pathology. Although considerable information is available about the conformation of α-syn at the initial and end stages of fibrillation, less is known about the dynamic process of α-syn conversion to oligomers and how interactions with antiaggregation chaperones such as β-synuclein might occur. Molecular modeling and molecular dynamics simulations based on the micelle-derived structure of α-syn showed that α-syn homodimers can adopt nonpropagating (head-to-tail) and propagating (head-to-head) conformations. Propagating α-syn dimers on the membrane incorporate additional α-syn molecules, leading to the formation of pentamers and hexamers forming a ring-like structure. In contrast, β-syn dimers do not propagate and block the aggregation of α-syn into ring-like oligomers. Under in vitro cell-free conditions, α-syn aggregates formed ring-like structures that were disrupted by β-syn. Similarly, cells expressing α-syn displayed increased ion current activity consistent with the formation of Zn2+-sensitive nonselective cation channels. These results support the contention that in Parkinson's disease and Lewy body dementia, α-syn oligomers on the membrane might form pore-like structures, and that the beneficial effects of β-synuclein might be related to its ability to block the formation of pore-like structures.

Original languageEnglish (US)
Pages (from-to)1862-1877
Number of pages16
JournalFEBS Journal
Volume274
Issue number7
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

Keywords

  • Cation channels
  • Modeling
  • Molecular dynamics
  • Oligomers
  • Synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tsigelny, I. F., Bar-On, P., Sharikov, Y., Crews, L., Hashimoto, M., Miller, M. A., Keller, S. H., Platoshyn, O., Yuan, J. X. J., & Masliah, E. (2007). Dynamics of α-synuclein aggregation and inhibition of pore-like oligomer development by β-synuclein. FEBS Journal, 274(7), 1862-1877. https://doi.org/10.1111/j.1742-4658.2007.05733.x