Cyclized NDGA modifies dynamic α-synuclein monomers preventing aggregation and toxicity.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
27 02 2019
27 02 2019
Historique:
received:
22
10
2018
accepted:
04
01
2019
entrez:
1
3
2019
pubmed:
1
3
2019
medline:
17
9
2020
Statut:
epublish
Résumé
Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson's disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated α-synuclein suppressed aggregation of naïve untreated aggregation-competent monomeric α-synuclein. Further, cyclized NDGA reduced α-synuclein-driven neurodegeneration in Caenorhabditis elegans. The cyclized NDGA analogs may serve as a platform for the development of small molecules that stabilize aggregation-resistant α-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders.
Identifiants
pubmed: 30814575
doi: 10.1038/s41598-019-39480-z
pii: 10.1038/s41598-019-39480-z
pmc: PMC6393491
doi:
Substances chimiques
Amyloid
0
Phospholipids
0
alpha-Synuclein
0
Masoprocol
7BO8G1BYQU
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2937Subventions
Organisme : NINDS NIH HHS
ID : R01 NS081033
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS081033
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG000255
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008076
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS079955
Pays : United States
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