Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy
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Section of Biochemistry, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
2
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
*
Authors to whom correspondence should be addressed.
Academic Editors: Giuliana Fusco and Stefano Gianni
Life 2021, 11(5), 431; https://doi.org/10.3390/life11050431
Received: 16 April 2021
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Revised: 30 April 2021
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Accepted: 4 May 2021
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Published: 11 May 2021
(This article belongs to the Special Issue Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins, Volume II)
α-Synuclein (αS) is an intrinsically disordered and highly dynamic protein involved in dopamine release at presynaptic terminals. The abnormal aggregation of αS as mature fibrils into intraneuronal inclusion bodies is directly linked to Parkinson’s disease. Increasing experimental evidence suggests that soluble oligomers formed early during the aggregation process are the most cytotoxic forms of αS. This study investigated the uptake by neuronal cells of pathologically relevant αS oligomers and fibrils exploiting a range of conformation-sensitive antibodies, and the super-resolution stimulated emission depletion (STED) microscopy. We found that prefibrillar oligomers promptly penetrate neuronal membranes, thus resulting in cell dysfunction. By contrast, fibril docking to the phospholipid bilayer is accompanied by αS conformational changes with a progressive release of A11-reactive oligomers, which can enter into the neurons and trigger cell impairment. Our data provide important evidence on the role of αS fibrils as a source of harmful oligomers, which resemble the intermediate conformers formed de novo during aggregation, underling the dynamic and reversible nature of protein aggregates responsible for α-synucleinopathies.
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Keywords:
synucleinopathies; protein aggregation; amyloid; toxic oligomers; Lewy bodies; PD; protein misfolding; neurodegeneration
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MDPI and ACS Style
Bigi, A.; Ermini, E.; Chen, S.W.; Cascella, R.; Cecchi, C. Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy. Life 2021, 11, 431. https://doi.org/10.3390/life11050431
AMA Style
Bigi A, Ermini E, Chen SW, Cascella R, Cecchi C. Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy. Life. 2021; 11(5):431. https://doi.org/10.3390/life11050431
Chicago/Turabian StyleBigi, Alessandra, Emilio Ermini, Serene W. Chen, Roberta Cascella, and Cristina Cecchi. 2021. "Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy" Life 11, no. 5: 431. https://doi.org/10.3390/life11050431
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