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 monomers without interfering with functional conformations yielding potential therapies for PD and related disorders.
Highlights
Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by a progressive motor phenotype including tremors, rigidity, and bradykinesia
To confirm the Thioflavin-T findings, the secondary structure of aggregates was quantified by circular dichroism (CD)
Using nordihydroguaiaretic acid (NDGA) and novel analogs, we uncovered that NDGA oxidation and cyclization was required for formation of quinone-modified monomeric α-synuclein
Summary
Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized by a progressive motor phenotype including tremors, rigidity, and bradykinesia. Induction of α-synuclein aggregation in wildtype animals by seeding with α-synuclein aggregates—isolated from PD Lewy bodies[24] or generated in vitro25–28— induces progressive neurodegeneration. A well-studied member of this groups is epigallocatechin gallate (EGCG), a polyphenol sharing the vicinal hydroxyls implicated in dopamine’s interaction with α-synuclein. Despite their chemical similarities, dopamine and EGCG have divergent effects on the structure of α-synuclein[49]. Recent studies have examined small molecules that directly stabilize α-synuclein monomers (e.g. BIOD30355, nortriptyline[56], CLR0157,58) It remains unknown whether these small molecules perturb α-synuclein’s lipid interactions, which are directly implicated in its role in neurotransmitter release[59,60,61]
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