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

被引：46

作者：

Daniels, Malcolm J. ^{[1
]}

Nourse, J. Brucker, Jr. ^{[2
]}

Kim, Hanna ^{[2
]}

Sainati, Valerio ^{[3
,4
]}

Schiavina, Marco ^{[3
,4
]}

Murrali, Maria Grazia ^{[3
,4
]}

Pan, Buyan ^{[5
]}

Ferrie, John J. ^{[5
]}

Haney, Conor M. ^{[5
]}

Moons, Rani ^{[6
]}

Gould, Neal S. ^{[7
]}

Natalello, Antonino ^{[8
]}

Grandori, Rita ^{[8
]}

Sobott, Frank ^{[9
,10
,11
]}

Petersson, E. James ^{[5
]}

Rhoades, Elizabeth ^{[5
]}

Pierattelli, Roberta ^{[3
,4
]}

Felli, Isabella ^{[3
,4
]}

Uversky, Vladimir N. ^{[12
,13
,14
]}

Caldwell, Kim A. ^{[2
]}

Caldwell, Guy A. ^{[2
]}

Krol, Edward S. ^{[15
]}

Ischiropoulos, Harry ^{[1
,7
,16
,17
]}

机构：

[1] Univ Penn, Raymond & Ruth Perelman Sch Med, Pharmacol Grad Grp, Philadelphia, PA 19104 USA

[2] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA

[3] Univ Florence, CERM, I-50019 Florence, Italy

[4] Univ Florence, Dept Chem Ugo Schiff, I-50019 Florence, Italy

[5] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA

[6] Univ Antwerp, Dept Chem, Antwerp, Belgium

[7] Childrens Hosp Philadelphia, Dept Pediat, Res Inst, Philadelphia, PA 19104 USA

[8] Univ Milano Bicocca, Dept Biotechnol & Biosci, Milan, Italy

[9] Antwerp Univ, Biomol & Analyt Mass Spectrometry, Antwerp, Belgium

[10] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds, W Yorkshire, England

[11] Univ Leeds, Sch Mol & Cellular Biol, Leeds, W Yorkshire, England

[12] Univ S Florida, Morsani Coll Med, Dept Mol Med, Tampa, FL 33612 USA

[13] Univ S Florida, Morsani Coll Med, Byrd Alzheimers Res Inst, Tampa, FL 33612 USA

[14] Russian Acad Sci, Inst Biol Instrumentat, Pushchino 142292, Moscow Region, Russia

[15] Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK, Canada

[16] Univ Penn, Childrens Hosp Philadelphia, Res Inst, Philadelphia, PA 19104 USA

[17] Univ Penn, Raymond & Ruth Perelman Sch Med, Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

基金：

加拿大自然科学与工程研究理事会;

关键词：

SMALL-MOLECULE INHIBITORS; MULTIPLE-SYSTEM ATROPHY; PARKINSONS-DISEASE; LEWY BODIES; IN-VIVO; EPIGALLOCATECHIN GALLATE; DISORDERED PROTEINS; COPPER(II) BINDING; NEURONAL INJURY; MUTATION;

D O I：

10.1038/s41598-019-39480-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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