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Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils

Amyloid Diseases involve the growth of disease specific proteins into amyloid fibrils and their deposition in protein plaques. Amyloid fibril formation is typically preceded by oligomeric intermediates. Despite significant efforts, the specific role fibrils or oligomers play in the etiology of any g...

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Autores principales: Muschol, Martin, Hoyer, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947291/
https://www.ncbi.nlm.nih.gov/pubmed/36845541
http://dx.doi.org/10.3389/fmolb.2023.1120416
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author Muschol, Martin
Hoyer, Wolfgang
author_facet Muschol, Martin
Hoyer, Wolfgang
author_sort Muschol, Martin
collection PubMed
description Amyloid Diseases involve the growth of disease specific proteins into amyloid fibrils and their deposition in protein plaques. Amyloid fibril formation is typically preceded by oligomeric intermediates. Despite significant efforts, the specific role fibrils or oligomers play in the etiology of any given amyloid disease remains controversial. In neurodegenerative disease, though, amyloid oligomers are widely considered critical contributors to disease symptoms. Aside from oligomers as inevitable on-pathway precursors of fibril formation, there is significant evidence for off-pathway oligomer formation competing with fibril growth. The distinct mechanisms and pathways of oligomer formation directly affect our understanding under which conditions oligomers emerge in vivo, and whether their formation is directly coupled to, or distinct from, amyloid fibril formation. In this review, we will discuss the basic energy landscapes underlying the formation of on-pathway vs. off-pathway oligomers, their relation to the related amyloid aggregation kinetics, and their resulting implications for disease etiology. We will review evidence on how differences in the local environment of amyloid assembly can dramatically shift the relative preponderance of oligomers vs. fibrils. Finally, we will comment on gaps in our knowledge of oligomer assembly, of their structure, and on how to assess their relevance to disease etiology.
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spelling pubmed-99472912023-02-24 Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils Muschol, Martin Hoyer, Wolfgang Front Mol Biosci Molecular Biosciences Amyloid Diseases involve the growth of disease specific proteins into amyloid fibrils and their deposition in protein plaques. Amyloid fibril formation is typically preceded by oligomeric intermediates. Despite significant efforts, the specific role fibrils or oligomers play in the etiology of any given amyloid disease remains controversial. In neurodegenerative disease, though, amyloid oligomers are widely considered critical contributors to disease symptoms. Aside from oligomers as inevitable on-pathway precursors of fibril formation, there is significant evidence for off-pathway oligomer formation competing with fibril growth. The distinct mechanisms and pathways of oligomer formation directly affect our understanding under which conditions oligomers emerge in vivo, and whether their formation is directly coupled to, or distinct from, amyloid fibril formation. In this review, we will discuss the basic energy landscapes underlying the formation of on-pathway vs. off-pathway oligomers, their relation to the related amyloid aggregation kinetics, and their resulting implications for disease etiology. We will review evidence on how differences in the local environment of amyloid assembly can dramatically shift the relative preponderance of oligomers vs. fibrils. Finally, we will comment on gaps in our knowledge of oligomer assembly, of their structure, and on how to assess their relevance to disease etiology. Frontiers Media S.A. 2023-02-09 /pmc/articles/PMC9947291/ /pubmed/36845541 http://dx.doi.org/10.3389/fmolb.2023.1120416 Text en Copyright © 2023 Muschol and Hoyer. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Muschol, Martin
Hoyer, Wolfgang
Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils
title Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils
title_full Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils
title_fullStr Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils
title_full_unstemmed Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils
title_short Amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils
title_sort amyloid oligomers as on-pathway precursors or off-pathway competitors of fibrils
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947291/
https://www.ncbi.nlm.nih.gov/pubmed/36845541
http://dx.doi.org/10.3389/fmolb.2023.1120416
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