Journal Article

FZJ-2026-00754

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Off-pathway oligomers of α-synuclein and Aβ inhibit secondary nucleation of α-synuclein amyloid fibrils

Schützmann, M. P. ; Hoyer, W. (Corresponding author)FZJ*

2025
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.jmb.2025.169048  doi:10.34734/FZJ-2026-00754

Abstract: α-Synuclein (αSyn) is a key culprit in the pathogenesis of synucleinopathies such as Parkinson’s Disease (PD), in which it forms not only insoluble aggregates called amyloid fibrils but also smaller, likely more detrimental species termed oligomers. This property is shared with other amyloidogenic proteins such as the Alzheimer’s Disease-associated amyloid-β (Aβ). We previously found an intriguing interplay between off-pathway Aβ oligomers and Aβ fibrils, in which the oligomers interfere with fibril formation via inhibition of secondary nucleation by blocking secondary nucleation sites on the fibril surface. Here, using ThT aggregation kinetics and atomic force microscopy (AFM), we tested if the same interplay applies to αSyn fibrils. Both homotypic (i.e. αSyn) and heterotypic (i.e. Aβ) off-pathway oligomers inhibited αSyn aggregation in kinetic assays of secondary nucleation. Initially soluble, kinetically trapped Aβ oligomers co-precipitated with αSyn(1–108) fibrils. The resulting co-assemblies were imaged as clusters of curvilinear oligomers by AFM. The results indicate that off-pathway oligomers have a general tendency to bind amyloid fibril surfaces, also in the absence of sequence homology between fibril and oligomer. The interplay between off-pathway oligomers and amyloid fibrils adds another level of complexity to the homo- and hetero-assembly processes of amyloidogenic proteins.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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