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

Autor: Daniels MJ; Pharmacology Graduate Group, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Nourse JB Jr; Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, 35487, USA., Kim H; Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, 35487, USA., Sainati V; CERM and Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Florence, 50019, Italy., Schiavina M; CERM and Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Florence, 50019, Italy., Murrali MG; CERM and Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Florence, 50019, Italy., Pan B; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA., Ferrie JJ; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA., Haney CM; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA., Moons R; Department of Chemistry, University of Antwerp, Antwerp, Belgium., Gould NS; Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA., Natalello A; Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy., Grandori R; Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy., Sobott F; Biomolecular & Analytical Mass Spectrometry, Antwerp University, Antwerp, Belgium.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.; School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom., Petersson EJ; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA., Rhoades E; Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA., Pierattelli R; CERM and Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Florence, 50019, Italy., Felli I; CERM and Department of Chemistry 'Ugo Schiff', University of Florence, Sesto Fiorentino, Florence, 50019, Italy., Uversky VN; Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.; Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, 142292, Russian Federation., Caldwell KA; Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, 35487, USA., Caldwell GA; Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, 35487, USA., Krol ES; College of Pharmacy & Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada., Ischiropoulos H; Pharmacology Graduate Group, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. ischirop@pennmedicine.upenn.edu.; Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA. ischirop@pennmedicine.upenn.edu.; Children's Hospital of Philadelphia Research Institute and Systems Pharmacology and Translational Therapeutics, the Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. ischirop@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Feb 27; Vol. 9 (1), pp. 2937. Date of Electronic Publication: 2019 Feb 27.
DOI: 10.1038/s41598-019-39480-z
Abstrakt: 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.
Databáze: MEDLINE
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