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Role of ?-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 ?-synuclein (?-syn) in the central nervous system. Aggregation of ?-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 ?-syn in membranes. The studies suggest that ?-syn penetrates the membrane rapidly, changing its conformation from ?-helical towards a coiled structure. This penetration facilitates the incorporation of additional ?-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 ?-syn. After 4 ns of simulation of the protein-membrane model, ?-syn had penetrated through two-thirds of the membrane. By 9 ns, the penetration of the annular ?-syn oligomers can result in the formation of pore-like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant ?-syn in synthetic membranes resulted in the formation of similar pore-like complexes. Moreover, mutant (A53T) ?-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 ?-syn oligomerization in the membrane, and support the role of formation of pore-like structures in the pathogenesis of the neurodegenerative process in PD.

SUBMITTER: Tsigelny IF

PROVIDER: S-EPMC3925782 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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

Tsigelny Igor F IF Sharikov Yuriy Y Wrasidlo Wolfgang W Gonzalez Tania T Desplats Paula A PA Crews Leslie L Spencer Brian B Masliah Eliezer E

The FEBS journal 20120227 6

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 ...[more]

PMID: 22251432

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

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

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