Cyclized NDGA modifies dynamic ?-synuclein monomers preventing aggregation and toxicity.

ABSTRACT: Growing evidence implicates ?-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 ?-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 ?-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of ?-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric ?-synuclein. NDGA analog-pretreated ?-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated ?-synuclein suppressed aggregation of naïve untreated aggregation-competent monomeric ?-synuclein. Further, cyclized NDGA reduced ?-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 ?-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders.

SUBMITTER: Daniels MJ 

PROVIDER: S-EPMC6393491 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature