Off-pathway α-synuclein oligomers seem to alter α-synuclein turnover in a cell model but lack seeding capability in vivo.
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.
Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University , Uppsala , Sweden .
Therese
T
Fagerqvist
Thomas
T
Näsström
Elisabet
E
Ihse
Veronica
V
Lindström
Charlotte
C
Sahlin
Stina M Fangmark
SM
Tucker
Alex
A
Kasaryan
Mikael
M
Karlsson
Fredrik
F
Nikolajeff
Heinrich
H
Schell
Tiago F
TF
Outeiro
Philipp J
PJ
Kahle
Lars
L
Lannfelt
Martin
M
Ingelsson
Joakim
J
Bergström
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
C403894:4-oxo-2-nonenal; D000447:Aldehydes; D051844:alpha-Synuclein