{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:35:12Z","timestamp":1790768112669,"version":"4.1.0"},"reference-count":67,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,2,27]],"date-time":"2012-02-27T00:00:00Z","timestamp":1330300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2012,3]]},"abstract":"<jats:p>Parkinson\u2019s disease (PD) and dementia with Lewy bodies are common disorders of the aging population and characterized by the progressive accumulation of \u03b1\u2010synuclein (\u03b1\u2010syn) in the central nervous system. Aggregation of \u03b1\u2010syn into oligomers with a ring\u2010like 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\u2010like structures are unclear. We utilized computer modeling and cell\u2010based studies to investigate the process of oligomerization of wild\u2010type and A53T mutant \u03b1\u2010syn in membranes. The studies suggest that \u03b1\u2010syn penetrates the membrane rapidly, changing its conformation from \u03b1\u2010helical towards a coiled structure. This penetration facilitates the incorporation of additional \u03b1\u2010syn 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\u2010type \u03b1\u2010syn. After 4\u2003ns of simulation of the protein\u2013membrane model, \u03b1\u2010syn had penetrated through two\u2010thirds of the membrane. By 9\u2003ns, the penetration of the annular \u03b1\u2010syn oligomers can result in the formation of pore\u2010like structures that fully perforate the lipid bilayer. Experimental incubation of recombinant \u03b1\u2010syn in synthetic membranes resulted in the formation of similar pore\u2010like complexes. Moreover, mutant (A53T) \u03b1\u2010syn 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 \u03b1\u2010syn oligomerization in the membrane, and support the role of formation of pore\u2010like structures in the pathogenesis of the neurodegenerative process in PD.<\/jats:p>","DOI":"10.1111\/j.1742-4658.2012.08489.x","type":"journal-article","created":{"date-parts":[[2012,1,17]],"date-time":"2012-01-17T22:42:32Z","timestamp":1326840152000},"page":"1000-1013","source":"Crossref","is-referenced-by-count":173,"title":["Role of \u03b1\u2010synuclein penetration into the membrane in the mechanisms of oligomer pore formation"],"prefix":"10.1111","volume":"279","author":[{"given":"Igor 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