Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation

The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and...

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Autores principales:	Fauerbach, J.A., Yushchenko, D.A., Shahmoradian, S.H., Chiu, W., Jovin, T.M., Jares-Erijman, E.A.
Formato:	JOUR
Materias:	alpha synuclein proton article atomic force microscopy chemical structure chemistry cryoelectron microscopy protein multimerization protein secondary structure time alpha-Synuclein Cryoelectron Microscopy Microscopy, Atomic Force Models, Molecular Protein Multimerization Protein Structure, Secondary Protons Time Factors
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00063495_v102_n5_p1127_Fauerbach
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00063495_v102_n5_p1127_Fauerbach
record_format	dspace
spelling	todo:paper_00063495_v102_n5_p1127_Fauerbach2023-10-03T14:05:02Z Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation Fauerbach, J.A. Yushchenko, D.A. Shahmoradian, S.H. Chiu, W. Jovin, T.M. Jares-Erijman, E.A. alpha synuclein proton article atomic force microscopy chemical structure chemistry cryoelectron microscopy protein multimerization protein secondary structure time alpha-Synuclein Cryoelectron Microscopy Microscopy, Atomic Force Models, Molecular Protein Multimerization Protein Structure, Secondary Protons Time Factors The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3-0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity. © 2012 Biophysical Society. Fil:Fauerbach, J.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Jares-Erijman, E.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00063495_v102_n5_p1127_Fauerbach
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	alpha synuclein proton article atomic force microscopy chemical structure chemistry cryoelectron microscopy protein multimerization protein secondary structure time alpha-Synuclein Cryoelectron Microscopy Microscopy, Atomic Force Models, Molecular Protein Multimerization Protein Structure, Secondary Protons Time Factors
spellingShingle	alpha synuclein proton article atomic force microscopy chemical structure chemistry cryoelectron microscopy protein multimerization protein secondary structure time alpha-Synuclein Cryoelectron Microscopy Microscopy, Atomic Force Models, Molecular Protein Multimerization Protein Structure, Secondary Protons Time Factors Fauerbach, J.A. Yushchenko, D.A. Shahmoradian, S.H. Chiu, W. Jovin, T.M. Jares-Erijman, E.A. Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
topic_facet	alpha synuclein proton article atomic force microscopy chemical structure chemistry cryoelectron microscopy protein multimerization protein secondary structure time alpha-Synuclein Cryoelectron Microscopy Microscopy, Atomic Force Models, Molecular Protein Multimerization Protein Structure, Secondary Protons Time Factors
description	The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ∼0.3-0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity. © 2012 Biophysical Society.
format	JOUR
author	Fauerbach, J.A. Yushchenko, D.A. Shahmoradian, S.H. Chiu, W. Jovin, T.M. Jares-Erijman, E.A.
author_facet	Fauerbach, J.A. Yushchenko, D.A. Shahmoradian, S.H. Chiu, W. Jovin, T.M. Jares-Erijman, E.A.
author_sort	Fauerbach, J.A.
title	Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
title_short	Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
title_full	Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
title_fullStr	Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
title_full_unstemmed	Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
title_sort	supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation
url	http://hdl.handle.net/20.500.12110/paper_00063495_v102_n5_p1127_Fauerbach
work_keys_str_mv	AT fauerbachja supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation AT yushchenkoda supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation AT shahmoradiansh supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation AT chiuw supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation AT jovintm supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation AT jareserijmanea supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation
_version_	1807316893099360256

Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation

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