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

• Published in: Amyloid 2013-12, Vol.20 (4), p.233-244
• Main Authors: Fagerqvist, Therese, Näsström, Thomas, Ihse, Elisabet, Lindström, Veronica, Sahlin, Charlotte, Fangmark Tucker, Stina M., Kasaryan, Alex, Karlsson, Mikael, Nikolajeff, Fredrik, Schell, Heinrich, Outeiro, Tiago F., Kahle, Philipp J., Lannfelt, Lars, Ingelsson, Martin, Bergström, Joakim
• Format: Article
• Language: English
• Subjects: Aggregation; Aldehydes - chemistry; alpha-synuclein; alpha-Synuclein - chemistry; alpha-Synuclein - metabolism; Animals; Biomedical Sciences; Biomedicinsk vetenskap; Brain - metabolism; Brain - pathology; Cell Line, Tumor; Engineering Science with specialization in Microsystems Technology; Geriatrics; Geriatrik; Humans; Mice; Mice, Transgenic; Microscopy, Atomic Force; Neuroscience; Neurovetenskap; oligomers; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; seeding; Teknisk fysik med inriktning mot mikrosystemteknik
• ISSN: 1350-6129; 1744-2818; 1744-2818
• DOI: 10.3109/13506129.2013.835726

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.