Cyclized NDGA modifies dynamic α-synuclein monomers preventing aggregation and toxicity

Scientific Reports
Malcolm J DanielsHarry Ischiropoulos

Abstract

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...Continue Reading

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Citations

Mar 19, 2020·International Journal of Molecular Sciences·Rebecca Sternke-HoffmannAlexander K Buell
Jul 11, 2019·Neural Regeneration Research·Francisca Pinheiro, Salvador Ventura
Dec 15, 2019·Biomolecules·Tomas SneiderisVytautas Smirnovas
Oct 3, 2020·Scientific Reports·Rani MoonsFrank Sobott
May 15, 2020·Biomolecules·Jianlin ChenJianhan Chen
Nov 21, 2020·International Journal of Molecular Sciences·Xiao-Yu DuRui-Tian Liu
Jun 7, 2021·Current Opinion in Chemical Biology·Marie Shimogawa, E James Petersson

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Methods Mentioned

BETA
circular dichroism
transmission electron microscopy
solubility assay
FRET
fluorescence correlation spectroscopy
NMR
size exclusion chromatography
FCS
Infrared Imaging
electrophoresis

Software Mentioned

NDGA
COR Odyssey
LI
Prism
GraphPad
ChemStation

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