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

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.