Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates

The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilament...

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Veröffentlicht in:Journal of the American Chemical Society 2024-04, Vol.146 (15), p.10537-10549
Hauptverfasser: Chen, Serene W., Barritt, Joseph D., Cascella, Roberta, Bigi, Alessandra, Cecchi, Cristina, Banchelli, Martina, Gallo, Angelo, Jarvis, James A., Chiti, Fabrizio, Dobson, Christopher M., Fusco, Giuliana, De Simone, Alfonso
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container_end_page 10549
container_issue 15
container_start_page 10537
container_title Journal of the American Chemical Society
container_volume 146
creator Chen, Serene W.
Barritt, Joseph D.
Cascella, Roberta
Bigi, Alessandra
Cecchi, Cristina
Banchelli, Martina
Gallo, Angelo
Jarvis, James A.
Chiti, Fabrizio
Dobson, Christopher M.
Fusco, Giuliana
De Simone, Alfonso
description The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates. These transient amyloid intermediates, which induce significant levels of cytotoxicity when incubated with neuronal cells, were found to be stabilized by a small core in an antiparallel β-sheet conformation, with a disordered N-terminal region of the protein remaining available to mediate membrane binding. In contrast, mature amyloids that subsequently appear during the aggregation showed different structural and biological properties, including low levels of cytotoxicity, a rearranged structured core embedding also the N-terminal region, and a reduced propensity to interact with the membrane. The characterization of these two fibrillar forms of αS, and the use of antibodies and designed mutants, enabled us to clarify the role of critical structural elements endowing intermediate amyloid species with the ability to interact with membranes and induce cytotoxicity.
doi_str_mv 10.1021/jacs.3c14703
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subjects alpha-Synuclein - chemistry
alpha-Synuclein - genetics
alpha-Synuclein - toxicity
Amyloid - chemistry
Humans
Neurodegenerative Diseases
Parkinson Disease - metabolism
Protein Conformation, beta-Strand
title Structure–Toxicity Relationship in Intermediate Fibrils from α‑Synuclein Condensates
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