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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2012
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paper:paper_00063495_v102_n5_p1127_Fauerbach2023-06-08T14:31:12Z Supramolecular non-amyloid intermediates in the early stages of α-synuclein aggregation Fauerbach, Jonathan Arturo Jares, Elizabeth Andrea 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. 2012 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00063495_v102_n5_p1127_Fauerbach 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, Jonathan Arturo Jares, Elizabeth Andrea 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. |
| author |
Fauerbach, Jonathan Arturo Jares, Elizabeth Andrea |
| author_facet |
Fauerbach, Jonathan Arturo Jares, Elizabeth Andrea |
| author_sort |
Fauerbach, Jonathan Arturo |
| 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 |
| publishDate |
2012 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00063495_v102_n5_p1127_Fauerbach http://hdl.handle.net/20.500.12110/paper_00063495_v102_n5_p1127_Fauerbach |
| work_keys_str_mv |
AT fauerbachjonathanarturo supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation AT jareselizabethandrea supramolecularnonamyloidintermediatesintheearlystagesofasynucleinaggregation |
| _version_ |
1768543113665576960 |