An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils.
AS69
D. melanogaster
Parkinson's disease
amyloid
inhibtion
molecular biophysics
neuroscience
nucleation
structural biology
β-wrapin
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
21 08 2019
21 08 2019
Historique:
received:
25
02
2019
accepted:
04
08
2019
pubmed:
8
8
2019
medline:
12
2
2020
entrez:
8
8
2019
Statut:
epublish
Résumé
Removing or preventing the formation of [Formula: see text]-synuclein aggregates is a plausible strategy against Parkinson's disease. To this end, we have engineered the [Formula: see text]-wrapin AS69 to bind monomeric [Formula: see text]-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of [Formula: see text]-synuclein and formation of visible [Formula: see text]-synuclein aggregates. In flies, AS69 reduced [Formula: see text]-synuclein aggregates and the locomotor deficit resulting from [Formula: see text]-synuclein expression in neuronal cells. In biophysical experiments in vitro, AS69 highly sub-stoichiometrically inhibited both primary and autocatalytic secondary nucleation processes, even in the presence of a large excess of monomer. We present evidence that the AS69-[Formula: see text]-synuclein complex, rather than the free AS69, is the inhibitory species responsible for sub-stoichiometric inhibition of secondary nucleation. These results represent a new paradigm that high affinity monomer binders can lead to strongly sub-stoichiometric inhibition of nucleation processes.
Identifiants
pubmed: 31389332
doi: 10.7554/eLife.46112
pii: 46112
pmc: PMC6721797
doi:
pii:
Substances chimiques
Amyloid
0
Recombinant Proteins
0
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : H2020 European Research Council
ID : 726368
Pays : International
Organisme : H2020 Marie Skłodowska-Curie Actions
ID : 706551
Pays : International
Organisme : RWTH Aachen University
ID : START-Program of the Faculty of Medicine
Pays : International
Organisme : H2020 European Research Council
ID : MCSA grant agreement No 706551
Pays : International
Organisme : European Commission
ID : 706551
Pays : International
Informations de copyright
© 2019, Agerschou et al.
Déclaration de conflit d'intérêts
EA, PF, TS, CG, DK, LH, VP, HS, DW, CD, AV, BF, WH, AB No competing interests declared
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