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Lipid vesicles affect the aggregation of 4-hydroxy-2-nonenal-modified alpha-synuclein oligomers
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.ORCID iD: 0000-0003-4075-159X
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
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2018 (English)In: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1864, no 9, p. 3060-3068Article in journal (Refereed) Published
Abstract [en]

Parkinsons disease (PD) and other synucleinopathies are characterized by accumulation of misfolded aggregates of alpha-synuclein (alpha-syn). The normal function of alpha-syn is still under investigation, but it has been generally linked to synaptic plasticity, neurotransmitter release and the maintenance of the synaptic pool. alpha-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 alpha-syn functional role and its propensity to aggregate. In this study, we investigated the aggregation process of alpha-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 alpha-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 alpha-syn also induced cytotoxic effects on differentiated SHSY-SY cells. Under conditions in which the aggregation process was delayed cell viability was reduced. By exploring the behavior and potential cytotoxic effects of HNE-alpha-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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2018. Vol. 1864, no 9, p. 3060-3068
Keywords [en]
alpha-Synuclein; Parkinsons disease; Lipids; Aggregation kinetics; Toxicity
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-151192DOI: 10.1016/j.bbadis.2018.06.020ISI: 000442056200028PubMedID: 29960040OAI: oai:DiVA.org:liu-151192DiVA, id: diva2:1248617
Note

Funding Agencies|Swedish Research Council [MH: 523-2013-2735]; Research Foundation of the Swedish Parkinsons Disease Association; Ostergotland Research Foundation for Parkinsons Disease; Parkinson Research Foundation; Swedish Alzheimer foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Konung Gustaf V och Drottning Victorias Frimurarestiftelse; Swedish Dementia Foundation; Linkoping University Neurobiology Centre; County Council of Ostergotland

Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2019-04-24

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Hallbeck, Martin

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Sardar Sinha, MaitrayeeVillamil Giraldo, Ana MariaÖllinger, KarinHallbeck, MartinCivitelli, Livia
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