Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
26 11 2019
26 11 2019
Historique:
received:
15
02
2019
accepted:
29
10
2019
entrez:
28
11
2019
pubmed:
28
11
2019
medline:
11
11
2020
Statut:
epublish
Résumé
Alpha-synuclein (αS) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinson's disease and other synucleinopathies. β-Synuclein (βS), which co-localizes with αS, has been shown to provide a neuroprotective effect, but the molecular mechanism by which this occurs remains elusive. Here we show that αS fibrils formed in the presence of βS are less cytotoxic, exhibit reduced cell seeding capacity and are more resistant to fibril shedding compared to αS fibrils alone. Using solid-state NMR, we found that the overall structure of the core of αS fibrils when co-incubated with βS is minimally perturbed, however, the dynamics of Lys and Thr residues, located primarily in the imperfect KTKEGV repeats of the αS N-terminus, are increased. Our results suggest that amyloid fibril dynamics may play a key role in modulating toxicity and seeding. Thus, enhancing the dynamics of amyloid fibrils may be a strategy for future therapeutic targeting of neurodegenerative diseases.
Identifiants
pubmed: 31772376
doi: 10.1038/s41598-019-54063-8
pii: 10.1038/s41598-019-54063-8
pmc: PMC6879756
doi:
Substances chimiques
Amyloid
0
alpha-Synuclein
0
beta-Synuclein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
17579Subventions
Organisme : NINDS NIH HHS
ID : R01 NS101134
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM110577
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS123770
Pays : United States
Organisme : NCCIH NIH HHS
ID : R01 AT006868
Pays : United States
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