|
Title
|
|
|
|
Cyclized NDGA modifies dynamic alpha-synuclein monomers preventing aggregation and toxicity
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Growing evidence implicates alpha-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 alpha-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 alpha-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of alpha-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric alpha-synuclein. NDGA analog-pretreated alpha-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated alpha-synuclein suppressed aggregation of naive untreated aggregation-competent monomeric a-synuclein. Further, cyclized NDGA reduced alpha-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 alpha-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Scientific reports. - London, 2011, currens
| |
|
Publication
|
|
|
|
London
:
Nature Publishing Group
,
2019
| |
|
ISSN
|
|
|
|
2045-2322
| |
|
DOI
|
|
|
|
10.1038/S41598-019-39480-Z
| |
|
Volume/pages
|
|
|
|
9
(2019)
, 17 p.
| |
|
Article Reference
|
|
|
|
2937
| |
|
ISI
|
|
|
|
000459799800086
| |
|
Pubmed ID
|
|
|
|
30814575
| |
|
Medium
|
|
|
|
E-only publicatie
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|