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

Aggregated alpha-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 alpha-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 alpha-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 alpha-synuclein oligomers were added to monomeric alpha-synuclein. In contrast, exogenously added alpha-synuclein oligomers did not induce aggregation in a cell model. However, cells overexpressing alpha-synuclein that were treated with the oligomers displayed reduced alpha-synuclein levels, indicating that internalized oligomers either decreased the expression or accelerated the degradation of transfected alpha-synuclein. Also in vivo there were no clear seeding effects, as intracerebral injections of alpha-synuclein oligomers into the neocortex of alpha-synuclein transgenic mice did not induce formation of proteinase K resistant alpha-synuclein pathology. Taken together, we could observe a seeding effect of the ONE-induced alpha-synuclein oligomers in a fibrillization assay, but neither in a cell nor in a mouse model.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
Aggregation
alpha-synuclein
oligomers
Parkinson's disease
seeding
Biomedical Sciences
Biomedicinsk vetenskap

Näsström, ThomasUppsala University(Swepub:lnu)thnaaa (författare)
Ihse, ElisabetUppsala University (författare)
Lindström, VeronicaUppsala University (författare)
Sahlin, CharlotteUppsala University (författare)
Tucker, Stina M. FangmarkBioArctic Neurosci AB, Stockholm (författare)
Kasaryan, AlexBioArctic Neurosci AB, Stockholm (författare)
Karlsson, MikaelUppsala University (författare)
Nikolajeff, FredrikUppsala University (författare)
Schell, HeinrichHertie Inst Clin Brain Res, Germany;German Ctr Neurodegenerat Dis, Germany (författare)
Outeiro, Tiago F.Univ Med Ctr Göttingen, Germany (författare)
Kahle, Philipp J.Hertie Inst Clin Brain Res, Germany;German Ctr Neurodegenerat Dis, Germany (författare)
Lannfelt, LarsUppsala University (författare)
Ingelsson, MartinUppsala University (författare)
Bergström, JoakimUppsala University (författare)
Uppsala UniversityBioArctic Neurosci AB, Stockholm (creator_code:org_t)

Av författaren/redakt...: Fagerqvist, Ther ...; Näsström, Thomas; Ihse, Elisabet; Lindström, Veron ...; Sahlin, Charlott ...; Tucker, Stina M. ...; visa fler...; Kasaryan, Alex; Karlsson, Mikael; Nikolajeff, Fred ...; Schell, Heinrich; Outeiro, Tiago F ...; Kahle, Philipp J ...; Lannfelt, Lars; Ingelsson, Marti ...; Bergström, Joaki ...; visa färre...

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