Cyclized NDGA Modifies Dynamic Α-synuclein Monomers Preventing Aggregation and Toxicity

Authors

Malcolm J. Daniels, University of Pennsylvania
J. Brucker Nourse, University of Alabama
Hanna Kim, University of Alabama
Valerio Sainati, University of Florence
Marco Schiavina, University of Florence
Maria Grazia Murrali, University of Florence
Buyan Pan, University of Pennsylvania
John J. Ferrie, University of Pennsylvania
Conor M. Haney, University of Pennsylvania
Rani Moons, University of Antwerp
Neal S. Gould, Children’s Hospital of Philadelphia Research Institute
Antonino Natalello, University of Milan-Bicocca
Rita Grandori, University of Milan-Bicocca
Frank Sobott, Antwerp University
E. James Petersson, University of Pennsylvania
Elizabeth Rhoades, University of Pennsylvania
Roberta Pierattelli, University of Florence
Isabella Felli, University of Florence
Vladimir N. Uversky, University of South FloridaFollow
Kim A. Caldwell, University of Alabama
Guy A. Caldwell, University of Alabama
Edward S. Krol, University of Saskatchewan
Harry Ischiropoulos, University of Pennsylvania

Document Type

Article

Publication Date

2019

Keywords

Neurochemistry, Parkinson's disease

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41598-019-39480-z

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.

Rights Information

This work is licensed under a Creative Commons Attribution 4.0 License.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Scientific Reports, v. 9, art. 2937

Scholar Commons Citation

Daniels, Malcolm J.; Nourse, J. Brucker; Kim, Hanna; Sainati, Valerio; Schiavina, Marco; Murrali, Maria Grazia; Pan, Buyan; Ferrie, John J.; Haney, Conor M.; Moons, Rani; Gould, Neal S.; Natalello, Antonino; Grandori, Rita; Sobott, Frank; Petersson, E. James; Rhoades, Elizabeth; Pierattelli, Roberta; Felli, Isabella; Uversky, Vladimir N.; Caldwell, Kim A.; Caldwell, Guy A.; Krol, Edward S.; and Ischiropoulos, Harry, "Cyclized NDGA Modifies Dynamic Α-synuclein Monomers Preventing Aggregation and Toxicity" (2019). Molecular Medicine Faculty Publications. 122.
https://digitalcommons.usf.edu/mme_facpub/122