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Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation.

Authors
  • Tsigelny, Igor F
  • Sharikov, Yuriy
  • Wrasidlo, Wolfgang
  • Gonzalez, Tania
  • Desplats, Paula A
  • Crews, Leslie
  • Spencer, Brian
  • Masliah, Eliezer
Type
Published Article
Journal
FEBS Journal
Publisher
Wiley (Blackwell Publishing)
Publication Date
Mar 01, 2012
Volume
279
Issue
6
Pages
1000–1013
Identifiers
DOI: 10.1111/j.1742-4658.2012.08489.x
PMID: 22251432
Source
Medline
License
Unknown

Abstract

Parkinson's disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of α-synuclein (α-syn) in the central nervous system. Aggregation of α-syn into oligomers with a ring-like appearance has been proposed to play a role in toxicity. However, the molecular mechanisms and the potential sequence of events involved in the formation of pore-like structures are unclear. We utilized computer modeling and cell-based studies to investigate the process of oligomerization of wild-type and A53T mutant α-syn in membranes. The studies suggest that α-syn penetrates the membrane rapidly, changing its conformation from α-helical towards a coiled structure. This penetration facilitates the incorporation of additional α-syn monomers in the complex, and the subsequent displacement of phospholipids and the formation of oligomers in the membrane. This process occurred more rapidly, and with a more favorable energy of interaction, for mutant A53T compared with wild-type α-syn. After 4 ns of simulation of the protein-membrane model, α-syn had penetrated through two-thirds of the membrane. By 9 ns, the penetration of the annular α-syn oligomers can result in the formation of pore-like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant α-syn in synthetic membranes resulted in the formation of similar pore-like complexes. Moreover, mutant (A53T) α-syn had a greater tendency to accumulate in neuronal membrane fractions in cell cultures, resulting in greater neuronal permeability, as demonstrated with the calcein efflux assay. These studies provide a sequential molecular explanation for the process of α-syn oligomerization in the membrane, and support the role of formation of pore-like structures in the pathogenesis of the neurodegenerative process in PD.

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