title: Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation.
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.
authors.affiliation: San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Sharikov
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: Tania
authors.initials: T
authors.lastname: Gonzalez
authors.forename: Paula A
authors.initials: PA
authors.lastname: Desplats
authors.forename: Leslie
authors.initials: L
authors.lastname: Crews
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D020961:Lewy Body Disease / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D017433:Protein Structure, Secondary; D051381:Rats; D014407:Tumor Cells, Cultured; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D051844:alpha-Synuclein