Paper Citing NAMD - Abstract
Tsigelny, Igor F.; Sharikov, Yuriy; Wrasidlo, Wolfgang; Gonzalez, Tania; Desplats, Paula A.; Crews, Leslie; Spencer, Brian; Masliah, Eliezer
Role of alpha-synuclein penetration into the membrane in the mechanisms of oligomer pore formation
FEBS JOURNAL, 279:1000-1013, MAR 2012
Parkinsons disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of a-synuclein (a-syn) in the central nervous system. Aggregation of a-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 a-syn in membranes. The studies suggest that a-syn penetrates the membrane rapidly, changing its conformation from a-helical towards a coiled structure. This penetration facilitates the incorporation of additional a-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 a-syn. After 4 ns of simulation of the proteinmembrane model, a-syn had penetrated through two-thirds of the membrane. By 9 ns, the penetration of the annular a-syn oligomers can result in the formation of pore-like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant a-syn in synthetic membranes resulted in the formation of similar pore-like complexes. Moreover, mutant (A53T) a-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 a-syn oligomerization in the membrane, and support the role of formation of pore-like structures in the pathogenesis of the neurodegenerative process in PD.
