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@ARTICLE{Schtzmann:1052089,
author = {Schützmann, Marie P. and Hoyer, Wolfgang},
title = {{O}ff-pathway oligomers of α-synuclein and {A}β inhibit
secondary nucleation of α-synuclein amyloid fibrils},
journal = {Journal of molecular biology},
volume = {437},
number = {10},
issn = {0022-2836},
address = {Amsterdam [u.a.]},
publisher = {Elsevier},
reportid = {FZJ-2026-00754},
pages = {169048 -},
year = {2025},
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.},
cin = {IBI-7},
ddc = {610},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5244 - Information Processing in Neuronal Networks
(POF4-524)},
pid = {G:(DE-HGF)POF4-5244},
typ = {PUB:(DE-HGF)16},
doi = {10.1016/j.jmb.2025.169048},
url = {https://juser.fz-juelich.de/record/1052089},
}