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The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of α-synuclein oligomers with distinct biochemical, morphological, and functional properties
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
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2011 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 50, no 3, 428-437 p.Article in journal (Refereed) Published
Abstract [en]

Oxidative stress has been implicated in the etiology of neurodegenerative disorders with alpha-synuclein pathology. Lipid peroxidation products such as 4-oxo-2-nonenal (ONE) and 4-hydroxy-2-nonenal (HNE) can covalently modify and structurally alter proteins. Herein, we have characterized ONE- or HNE-induced alpha-synuclein oligomers. Our results demonstrate that both oligomers are rich in beta-sheet structure and have a molecular weight of about 2000 kDa. Atomic force microscopy analysis revealed that ONE-induced alpha-synuclein oligomers were relatively amorphous, with a diameter of 40-80 nm and a height of 4-8 nm. In contrast, the HNE-induced alpha-synuclein oligomers had a protofibril-like morphology with a width of 100-200 nm and a height of 2-4 nm. Furthermore, neither oligomer type polymerized into amyloid-like fibrils despite prolonged incubation. Although more SDS and urea stable, because of a higher degree of cross-linking, ONE-induced alpha-synuclein oligomers were less compact and more sensitive to proteinase K treatment. Finally, both ONE- and HNE-induced alpha-synuclein oligomers were cytotoxic when added exogenously to a neuroblastoma cell line, but HNE-induced alpha-synuclein oligomers were taken up by the cells to a significantly higher degree. Despite nearly identical chemical structures, ONE and HNE induce the formation of off-pathway alpha-synuclein oligomers with distinct biochemical, morphological, and functional properties.

Place, publisher, year, edition, pages
2011. Vol. 50, no 3, 428-437 p.
Keyword [en]
alpha-Synuclein, Oligomers, Lewy bodies, Lipid peroxidation, 4-Oxo-2-nonenal, Oxidative stress, 4-Hydroxy-2-nonenal, Free radicals
National Category
Medical and Health Sciences Materials Engineering
Research subject
Engineering Science with specialization in Microsystems Technology
URN: urn:nbn:se:uu:diva-148623DOI: 10.1016/j.freeradbiomed.2010.11.027ISI: 000287429600003PubMedID: 21130160OAI: oai:DiVA.org:uu-148623DiVA: diva2:402439
Available from: 2011-03-08 Created: 2011-03-08 Last updated: 2016-04-20Bibliographically approved
In thesis
1. Characterization of α-synuclein oligomers: Implications for Lewy Body Disorders
Open this publication in new window or tab >>Characterization of α-synuclein oligomers: Implications for Lewy Body Disorders
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy are disorders featuring accumulation of Lewy bodies in brain. The main component of these large insoluble intracellular inclusions is the presynaptic protein alpha-synuclein (α-synuclein). It is generally believed that α-synuclein monomers adopt an abnormal conformation that favors the formation of soluble oligomers or protofibrils and, eventually, insoluble fibrils depositing as Lewy bodies. Notably, the intermediately sized oligomers/protofibrils seem to have particular neurotoxic effects. Several factors may influence the formation of α-synuclein oligomers/protofibrils, e.g. the reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) formed during oxidative stress.

The overall aims of this thesis were to investigate biophysical and biochemical properties of in vitro generated α-synuclein oligomers, characterize their functional effects on cell and animal disease models as well as to explore whether their formation could be prevented in a cell culture model for oligomerization. 

Here, it was found that α-synuclein rapidly formed oligomers after incubation with both ONE and HNE. The resulting oligomers were stable and did not continue to form insoluble fibrils. By comparing HNE- and ONE induced α-synuclein oligomers biochemically they were both found to exhibit extensive β-beta sheet structure and had a molecular size of ~2000 kDa. However, they differed in morphology; the ONE induced α-synuclein oligomers described round amorphous species whereas the HNE induced α-synuclein oligomers appeared as elongated protofibril-like structures. Both these oligomers were cell internalized to varying degrees and induced toxicity in neuroblastoma cells.

In addition, the ONE induced α-synuclein oligomers seemed to initiate aggregation of monomeric α-synuclein in vitro, but failed to do so in vivo.

Finally, treatment of α-synuclein overexpressing cells with monoclonal antibodies specific for α-synuclein significantly reduced aggregation and lowered levels of the protein, suggesting increased turnover in these cells. 

To conclude, this thesis has characterized different oligomeric α-synuclein species, which may have properties similar to soluble species central to the pathogenesis of Parkinson’s disease and other disorders with α-synuclein pathology. For therapeutic strategies it is important to selectively target such harmful protein species and avoid interaction with other forms of α-synuclein, which may have vital physiological cellular functions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 70 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 717
Parkinson’s disease; Alpha-synuclein; Lewy bodies; Oligomers; Reactive aldehydes; monoclonal antibody
National Category
Neurosciences Geriatrics
Research subject
Medical Science
urn:nbn:se:uu:diva-160102 (URN)978-91-554-8198-8 (ISBN)
Public defence
2011-12-02, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 13:15 (English)
Available from: 2011-11-11 Created: 2011-10-16 Last updated: 2011-11-23Bibliographically approved

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Näsström, ThomasFagerqvist, ThereseKarlsson, MikaelNikolajeff, FredrikLannfelt, LarsIngelsson, MartinBergström, Joakim
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