Off-pathway α-synuclein oligomers seem to alter α-synuclein turnover in a cell model but lack seeding capability in vivo

Therese Fagerqvist, Thomas Näsström, Elisabet Ihse, Veronica Lindström, Charlotte Sahlin, Stina M. Fangmark Tucker, Alex Kasaryan, Mikael Karlsson, Fredrik Nikolajeff, Heinrich Schell, Tiago F. Outeiro, Philipp J. Kahle, Lars Lannfelt, Martin Ingelsson, Joakim Bergström*

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)233-244
Number of pages12
JournalAmyloid
Volume20
Issue number4
DOIs
Publication statusPublished - Dec 2013
Externally publishedYes

Keywords

  • Aggregation
  • Alpha-synuclein
  • Oligomers
  • Parkinson's disease
  • Seeding

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    Fagerqvist, T., Näsström, T., Ihse, E., Lindström, V., Sahlin, C., Fangmark Tucker, S. M., ... Bergström, J. (2013). Off-pathway α-synuclein oligomers seem to alter α-synuclein turnover in a cell model but lack seeding capability in vivo. Amyloid, 20(4), 233-244. https://doi.org/10.3109/13506129.2013.835726