Interaction of alpha-synuclein with biomembranes in Parkinson's disease -role of cardiolipin

One of the key molecular events underlying the pathogenesis of Parkinson's disease (PD) is the aberrant misfolding and aggregation of the alpha-synuclein (alpha S) 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 alpha S 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 alpha S-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 alpha S with a liquid-disordering phospholipid uniquely enriched in mitochondrial membranes, namely cardiolipin (1,3-diphosphatidyl-sn-glycerol, CL), helps target the aS oligomeric complexes intracellularly to mitochondria. Binding mediated by CL may thus represent an important pathomechanism by which cytosolic aS 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. (C) 2015 Elsevier Ltd. All rights reserved.