title: Functionally different α-synuclein inclusions yield insight into Parkinson's disease pathology.
abstract: The formation of α-synuclein (α-S) amyloid aggregates, called Lewy bodies (LBs), is a hallmark of Parkinson's disease (PD). The function of LBs in the disease process is however still unclear; they have been associated with both neuroprotection and toxicity. To obtain insight into this contradiction, we induced the formation of α-S inclusions, using three different induction methods in SH-SY5Y cells and rat-derived primary neuronal cells. Using confocal and STED microscopy we observed induction-dependent differences in α-S inclusion morphology, location and function. The aggregation of α-S in functionally different compartments correlates with the toxicity of the induction method measured in viability assays. The most cytotoxic treatment largely correlates with the formation of proteasome-associated, juxta-nuclear inclusions. With less toxic methods cytosolic deposits that are not associated with the proteasome are more prevalent. The distribution of α-S over at least two different types of inclusions is not limited to cell models, but is also observed in primary neuronal cells and in human mesencephalon. The existence of functionally different LBs, in vivo and in vitro, gives important insights in the impact of Lewy Body formation on neuronal functioning and may thereby provide a platform for discovering therapeutics.
authors.affiliation: Nanobiophysics Group, MESA+ Institute for Nanotechnology &MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Raiss
authors.affiliation: Nanobiophysics Group, MESA+ Institute for Nanotechnology &MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Theresa S
authors.initials: TS
authors.lastname: Braun
authors.affiliation: Nanobiophysics Group, MESA+ Institute for Nanotechnology &MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Irene B M
authors.initials: IB
authors.lastname: Konings
authors.affiliation: Lehrstuhl für Zellbiophysik E27, Technische Universität München, 85748 Garching, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Grabmayr
authors.affiliation: Biomedical Signal and Systems, and Neurophysiology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Gerco C
authors.initials: GC
authors.lastname: Hassink
authors.affiliation: Nanobiophysics Group, MESA+ Institute for Nanotechnology &MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Arshdeep
authors.initials: A
authors.lastname: Sidhu
authors.affiliation: Biomedical Signal and Systems, and Neurophysiology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: le Feber
authors.affiliation: Lehrstuhl für Zellbiophysik E27, Technische Universität München, 85748 Garching, Germany.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Bausch
authors.affiliation: Laboratorium Pathologie Oost-Nederland, Postbus 516, 7550 AM Hengelo, The Netherlands.
authors.forename: Casper
authors.initials: C
authors.lastname: Jansen
authors.affiliation: Nanobiophysics Group, MESA+ Institute for Nanotechnology &MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.|FOM Institute AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Subramaniam
authors.affiliation: Nanobiophysics Group, MESA+ Institute for Nanotechnology &MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Mireille M A E
authors.initials: MM
authors.lastname: Claessens
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism; D018625:Microscopy, Atomic Force; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex