Kinetic measurements give new insights into lipid membrane permeabilization by alpha-synuclein oligomers

M.T. Stöckl, Mireille Maria Anna Elisabeth Claessens, Vinod Subramaniam

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

Abstract

Interactions of oligomeric aggregates of the intrinsically disordered protein α-synuclein with lipid membranes appear to play an important role in the development of Parkinson's disease. The permeabilization of cellular membranes by oligomers has been proposed to result in neuronal death. The detailed mechanisms by which α-synuclein oligomers permeabilize lipid bilayers remain unknown. Two different mechanisms are conceivable. Oligomers may either insert into membranes forming pores through which small molecules can cross the membrane or their interaction with the membrane may disorder the lipid packing, giving rise to membrane defects. Here we show, using kinetic leakage measurements, that α-synuclein oligomer induced impairment of membrane integrity is not limited to the formation of permanent membrane spanning pores. Fast membrane permeabilization could be observed in a fraction of the large unilamellar vesicles. We have also observed, for the first time, that α-synuclein oligomers cause an enhanced lipid flip-flop. In neuronal cells, most of the α-synuclein is not expected to be present in an oligomeric form, but as monomers. In our in vitro experiments, we find that membrane bound monomeric α-synuclein can only delay the onset of oligomer-induced membrane permeabilization, implying that α-synuclein monomers cannot counteract oligomer toxicity
Original languageEnglish
Pages (from-to)338-345
JournalMolecular biosystems
Volume8
Issue number1
DOIs
Publication statusPublished - 2012

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alpha-Synuclein
Synucleins
Membrane Lipids
Membranes
Intrinsically Disordered Proteins
Lipids
Unilamellar Liposomes
Lipid Bilayers
Parkinson Disease

Keywords

  • IR-84640
  • METIS-278596

Cite this

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title = "Kinetic measurements give new insights into lipid membrane permeabilization by alpha-synuclein oligomers",
abstract = "Interactions of oligomeric aggregates of the intrinsically disordered protein α-synuclein with lipid membranes appear to play an important role in the development of Parkinson's disease. The permeabilization of cellular membranes by oligomers has been proposed to result in neuronal death. The detailed mechanisms by which α-synuclein oligomers permeabilize lipid bilayers remain unknown. Two different mechanisms are conceivable. Oligomers may either insert into membranes forming pores through which small molecules can cross the membrane or their interaction with the membrane may disorder the lipid packing, giving rise to membrane defects. Here we show, using kinetic leakage measurements, that α-synuclein oligomer induced impairment of membrane integrity is not limited to the formation of permanent membrane spanning pores. Fast membrane permeabilization could be observed in a fraction of the large unilamellar vesicles. We have also observed, for the first time, that α-synuclein oligomers cause an enhanced lipid flip-flop. In neuronal cells, most of the α-synuclein is not expected to be present in an oligomeric form, but as monomers. In our in vitro experiments, we find that membrane bound monomeric α-synuclein can only delay the onset of oligomer-induced membrane permeabilization, implying that α-synuclein monomers cannot counteract oligomer toxicity",
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Kinetic measurements give new insights into lipid membrane permeabilization by alpha-synuclein oligomers. / Stöckl, M.T.; Claessens, Mireille Maria Anna Elisabeth; Subramaniam, Vinod.

In: Molecular biosystems, Vol. 8, No. 1, 2012, p. 338-345.

Research output: Contribution to journalArticleAcademicpeer-review

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