Lipid vesicles affect the aggregation of 4-hydroxy-2-nonenal-modified α-synuclein oligomers

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2018-09, Vol.1864 (9), p.3060-3068
• Main Authors: Sardar Sinha, Maitrayee, Villamil Giraldo, Ana Maria, Öllinger, Karin, Hallbeck, Martin, Civitelli, Livia
• Format: Article
• Language: English
• Subjects: Aggregation kinetics; Aldehydes - metabolism; alpha-Synuclein - metabolism; alpha-Synuclein - ultrastructure; Cell Line, Tumor; Cell Survival - drug effects; Humans; Hydrogen-Ion Concentration; Lipid Metabolism - physiology; Lipid Peroxidation; Lipids; Liposomes - pharmacology; Microscopy, Electron, Transmission; Oxidative Stress; Parkinson Disease - pathology; Parkinson's disease; Protein Aggregation, Pathological - drug therapy; Protein Aggregation, Pathological - pathology; Protein Multimerization - drug effects; Protein Multimerization - physiology; Recombinant Proteins - metabolism; Synaptic Vesicles - pathology; Toxicity; α-Synuclein
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2018.06.020

Parkinson's disease (PD) and other synucleinopathies are characterized by accumulation of misfolded aggregates of α-synuclein (α-syn). The normal function of α-syn is still under investigation, but it has been generally linked to synaptic plasticity, neurotransmitter release and the maintenance of the synaptic pool. α-Syn localizes at synaptic terminals where it can bind to synaptic vesicles as well as to other cellular membranes. It has become clear that these interactions have an impact on both α-syn functional role and its propensity to aggregate. In this study, we investigated the aggregation process of α-syn covalently modified with 4-hydroxy-2-nonenal (HNE). HNE is a product of lipid peroxidation and has been implicated in the pathogenesis of different neurodegenerative diseases by modifying the kinetics of soluble toxic oligomers. Although HNE-modified α-syn has been reported to assemble into stable oligomers, we found that slightly acidic conditions promoted further protein aggregation. Lipid vesicles delayed the aggregation process in a concentration-dependent manner, an effect that was observed only when they were added at the beginning of the aggregation process. Co-aggregation of lipid vesicles with HNE-modified α-syn also induced cytotoxic effects on differentiated SHSY-5Y cells. Under conditions in which the aggregation process was delayed cell viability was reduced. By exploring the behavior and potential cytotoxic effects of HNE-α-syn under acidic conditions in relation to protein-lipid interactions our study gives a framework to examine a possible pathway leading from a physiological setting to the pathological outcome of PD. •Chemically-modified alpha-synuclein oligomers aggregate under acidic conditions.•Lipids delay the aggregation process of the modified alpha-synuclein oligomers.•The modified alpha-synuclein oligomers are toxic when incubated with lipids.