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Off-pathway alpha-synuclein oligomers seem to alter alpha-synuclein turnover in a cell model but lack seeding capability in vivo
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Lannfelt)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Lannfelt)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Lannfelt)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. (Lannfelt)
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2013 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 20, no 4, 233-244 p.Article in journal (Refereed) Published
Abstract [en]

Aggregated α-synuclein is the major component of Lewy bodies, protein inclusions observed in the brain in neurodegenerative disorders such as Parkinson’s disease and dementia with Lewy bodies. Experimental evidence indicates that α-synuclein potentially can be transferred between cells and act as a seed to accelerate the aggregation process. Here, we investigated in vitro and in vivo seeding effects of α-synuclein oligomers induced by the reactive aldehyde 4-oxo-2-nonenal (ONE). As measured by a Thioflavin-T based fibrillization assay, there was an earlier onset of aggregation when α-synuclein oligomers were added to monomeric α-synuclein. In contrast, exogenously added α-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing α-synuclein that were treated with the oligomers displayed reduced α-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected α-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of α-synuclein oligomers into the neocortex of α-synuclein transgenic mice did not induce formation of Proteinase K resistant α-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced α-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.

Place, publisher, year, edition, pages
2013. Vol. 20, no 4, 233-244 p.
Keyword [en]
Aggregation, alpha-synuclein, oligomers, Parkinson’s disease, seeding
National Category
Cell and Molecular Biology Neurosciences Engineering and Technology
Research subject
Geriatrics; Neuroscience; Engineering Science with specialization in Microsystems Technology
Identifiers
URN: urn:nbn:se:uu:diva-160100DOI: 10.3109/13506129.2013.835726ISI: 000327304800006OAI: oai:DiVA.org:uu-160100DiVA: diva2:450415
Available from: 2011-10-20 Created: 2011-10-16 Last updated: 2017-12-08
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 717
Keyword
Parkinson’s disease; Alpha-synuclein; Lewy bodies; Oligomers; Reactive aldehydes; monoclonal antibody
National Category
Neurosciences Geriatrics
Research subject
Medical Science
Identifiers
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)
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Available from: 2011-11-11 Created: 2011-10-16 Last updated: 2011-11-23Bibliographically approved

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Fagerqvist, ThereseNäsström, ThomasIhse, ElisabetLindström, VeronicaSahlin, CharlotteKarlsson, MikaelNikolajeff, FredrikLannfelt, LarsIngelsson, MartinBergström, Joakim

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Fagerqvist, ThereseNäsström, ThomasIhse, ElisabetLindström, VeronicaSahlin, CharlotteKarlsson, MikaelNikolajeff, FredrikLannfelt, LarsIngelsson, MartinBergström, Joakim
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