title: Interaction of α-synuclein with biomembranes in Parkinson's disease--role of cardiolipin.
abstract: One of the key molecular events underlying the pathogenesis of Parkinson's disease (PD) is the aberrant misfolding and aggregation of the α-synuclein (αS) protein into higher-order oligomers that play a key role in neuronal dysfunction and degeneration. A wealth of experimental data supports the hypothesis that the neurotoxicity of αS oligomers is intrinsically linked with their ability to interact with, and disrupt, biological membranes; especially those membranes having negatively-charged surfaces and/or lipid packing defects. Consequences of αS-lipid interaction include increased membrane tension, permeation by pore formation, membrane lysis and/or leakage due to the extraction of lipids from the bilayer. Moreover, we assert that the interaction of αS with a liquid-disordering phospholipid uniquely enriched in mitochondrial membranes, namely cardiolipin (1,3-diphosphatidyl-sn-glycerol, CL), helps target the αS oligomeric complexes intracellularly to mitochondria. Binding mediated by CL may thus represent an important pathomechanism by which cytosolic αS could physically associate with mitochondrial membranes and disrupt their integrity. Impaired mitochondrial function culminates in a cellular bioenergetic crisis and apoptotic death. To conclude, we advocate the accelerated discovery of new drugs targeting this pathway in order to restore mitochondrial function in PD.
authors.affiliation: Dept. of Physiology and Biochemistry, University of Malta, Msida, Malta.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ghio
authors.affiliation: Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University & DZNE, 81377 Munich, Germany.
authors.forename: Frits
authors.initials: F
authors.lastname: Kamp
authors.affiliation: Dept. of Physiology and Biochemistry, University of Malta, Msida, Malta.
authors.forename: Ruben
authors.initials: R
authors.lastname: Cauchi
authors.affiliation: Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.affiliation: Dept. of Physiology and Biochemistry, University of Malta, Msida, Malta. Electronic address: neville.vassallo@um.edu.mt.
authors.forename: Neville
authors.initials: N
authors.lastname: Vassallo
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D002308:Cardiolipins; D051844:alpha-Synuclein
keywords: Alpha-synuclein; Cardiolipin; Membrane permeabilization; Mitochondria; Oligomers; Parkinson's disease