title: Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons.
abstract: New strategies for visualizing self-assembly processes at the nanoscale give deep insights into the molecular origins of disease. An example is the self-assembly of misfolded proteins into amyloid fibrils, which is related to a range of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. Here, we probe the links between the mechanism of α-synuclein (AS) aggregation and its associated toxicity by using optical nanoscopy directly in a neuronal cell culture model of Parkinson's disease. Using superresolution microscopy, we show that protein fibrils are taken up by neuronal cells and act as prion-like seeds for elongation reactions that both consume endogenous AS and suppress its de novo aggregation. When AS is internalized in its monomeric form, however, it nucleates and triggers the aggregation of endogenous AS, leading to apoptosis, although there are no detectable cross-reactions between externally added and endogenous protein species. Monomer-induced apoptosis can be reduced by pretreatment with seed fibrils, suggesting that partial consumption of the externally added or excess soluble AS can be significantly neuroprotective.
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom;
authors.forename: Dorothea
authors.initials: D
authors.lastname: Pinotsi
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom;
authors.forename: Claire H
authors.initials: CH
authors.lastname: Michel
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Buell
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom;
authors.forename: Romain F
authors.initials: RF
authors.lastname: Laine
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom;
authors.forename: Pierre
authors.initials: P
authors.lastname: Mahou
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom;
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom; gsk20@cam.ac.uk.
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Kaminski Schierle
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000473:pathology*; D021381:Protein Transport; D057165:Proteostasis Deficiencies / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein
keywords: neurodegenerative disease; optical nanoscopy; prion-like behavior; seeding; α-synuclein