scholarly journals Conformational distortion in a fibril-forming oligomer arrests alpha-Synuclein fibrillation and minimizes its toxic effects

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Ritobrita Chakraborty ◽  
Sandip Dey ◽  
Pallabi Sil ◽  
Simanta Sarani Paul ◽  
Dipita Bhattacharyya ◽  
...  
Keyword(s):  
Small Molecule ◽  
Solid State Nmr ◽  
Amyloid Fibril ◽  
Alpha Synuclein ◽  
Fibril Formation ◽  
Stoichiometric Ratio ◽  
Oligomeric State ◽  
C Terminus ◽  
Amyloid Fibril Formation ◽  
Oligomeric Forms

AbstractThe fibrillation pathway of alpha-Synuclein, the causative protein of Parkinson’s disease, encompasses transient, heterogeneous oligomeric forms whose structural understanding and link to toxicity are not yet understood. We report that the addition of the physiologically-available small molecule heme at a sub-stoichiometric ratio to either monomeric or aggregated α-Syn, targets a His50 residue critical for fibril-formation and stabilizes the structurally-heterogeneous populations of aggregates into a minimally-toxic oligomeric state. Cryo-EM 3D reconstruction revealed a ‘mace’-shaped structure of this monodisperse population of oligomers, which is comparable to a solid-state NMR Greek key-like motif (where the core residues are arranged in parallel in-register sheets with a Greek key topology at the C terminus) that forms the fundamental unit/kernel of protofilaments. Further structural analyses suggest that heme binding induces a distortion in the Greek key-like architecture of the mace oligomers, which impairs their further appending into protofilaments and fibrils. Additionally, our study reports a novel mechanism of prevention as well as reclamation of amyloid fibril formation by blocking an inter-protofilament His50 residue using a small molecule.

Ion Mobility Mass Spectrometry Studies of the Inhibition of Alpha Synuclein Amyloid Fibril Formation by ( - )-Epigallocatechin-3-Gallate

2011 ◽  
Vol 64 (1) ◽  
pp. 36 ◽  
Author(s):  
Yanqin Liu ◽  
Lam H. Ho ◽  
John. A. Carver ◽  
Tara L. Pukala
Keyword(s):  
Mass Spectrometry ◽  
Conformational Change ◽  
Ion Mobility ◽  
Amyloid Fibril ◽  
Heterogeneous Systems ◽  
Alpha Synuclein ◽  
Fibril Formation ◽  
Ion Mobility Mass Spectrometry ◽  
Compact Structure ◽  
Amyloid Fibril Formation

Ion mobility-mass spectrometry (IM-MS) is emerging as an important biophysical technique for the structural analysis of proteins and their assemblies, in particular for structurally heterogeneous systems such as those on the protein misfolding and aggregation pathway. Using IM-MS we have monitored amyloid fibril formation of A53T α-synuclein, a mutant synuclein protein associated with Parkinson’s disease, and identified that a conformational change towards a more compact structure occurs during the initial stages of aggregation. Binding of A53T α-synuclein to a flavenoid based amyloid fibril inhibitor, (–)-epigallocatechin-3-gallate, has been observed with a 1:1 stoichiometry. By analysis of ion collision cross-sections, we show epigallocatechin gallate binding prevents protein conformational change, and in turn decreases the formation of fibrillar aggregates.

scholarly journals Acceleration of amyloid fibril formation by multichannel sonochemical reactor

2021 ◽  
Author(s):  
Kentaro Noi ◽  
Kichitaro Nakajima ◽  
Keiichi Yamaguchi ◽  
Masatomo So ◽  
Kensuke Ikenaka ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Ultrasonic Transducer ◽  
Reaction System ◽  
Ultrasound Irradiation ◽  
Alpha Synuclein ◽  
Fibril Formation ◽  
Driving Voltage ◽  
Amyloid Fibril Formation ◽  
Beta 2 Microglobulin

Abstract Formation of amyloid fibrils of various amyloidogenic proteins is dramatically enhanced by ultrasound irradiation. For applying this phenomenon to the study of protein aggregation science and diagnosis of neurodegenerative diseases, a multichannel ultrasound irradiation system with individually adjustable ultrasound-irradiation conditions is necessary. Here, we develop a sonochemical reaction system, where an ultrasonic transducer is placed in each well of a 96-well microplate to perform ultrasonic irradiation of sample solutions under various conditions with high reproducibility, and applied it for studying amyloid-fibril formation of amyloid $\beta$, $\alpha$-synuclein, $\beta$2-microglobulin, and lysozyme. The results clearly show that our instrument is superior to conventional shaking method in terms of degree of acceleration and reproducibility of fibril formation reaction. The acceleration degree is controllable by controlling the driving voltage applied to each transducer. We have thus succeeded in developing a useful tool for the study of amyloid fibril formation in various proteins.

scholarly journals CryoEM reveals how the small molecule EGCG binds to Alzheimer’s brain-derived tau fibrils and initiates fibril disaggregation

2020 ◽  
Author(s):  
PM Seidler ◽  
DR Boyer ◽  
MR Sawaya ◽  
P Ge ◽  
WS Shin ◽  
...  
Keyword(s):  
Small Molecules ◽  
Green Tea ◽  
Small Molecule ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Fibril Formation ◽  
Paired Helical Filament ◽  
Amyloid Fibril Formation ◽  
Molecular Action ◽  
Tau Fibrils

AbstractEGCG, the most abundant favanol in green tea, is one of the few natural compounds known to inhibit amyloid fibril formation of proteins associated with neurodegeneration, and to disaggregate amyloid fibrils. Little is known of the mechanism of molecular action of EGCG, or how it or other small molecules interact with amyloid fibrils. Here we present a 3.9 Å resolution cryoEM structure that reveals the site of EGCG binding to Alzheimer’s disease (AD) brain-derived tau fibrils. The structure suggests that EGCG disaggregates fibrils of AD-tau by wedging into a cleft that is at the interface of two protofilaments of the paired helical filament, and by causing charge repulsions between tau layers of the fibril. In support of this, we observe separation of the protofilaments that EGCG wedges between, and accompanying displacement of the adjacent β-helix domain. By resolving the site of EGCG binding, our structure defines a pharmacophore-like cleft in the AD-tau fibril that will be of use for the discovery of surrogate compounds with more desirable drug-like properties.

scholarly journals Natural Alkaloid Compounds as Inhibitors for Alpha-Synuclein Seeded Fibril Formation and Toxicity

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3736
Author(s):  
Simona S. Ghanem ◽  
Hend S. Fayed ◽  
Qi Zhu ◽  
Jia-Hong Lu ◽  
Nishant N. Vaikath ◽  
...  
Keyword(s):  
Cell Viability ◽  
Therapeutic Strategy ◽  
Amyloid Fibril ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Fibril Formation ◽  
Amyloid Fibril Formation ◽  
Dependent Cell ◽  
Natural Alkaloid

The accumulation and aggregation of α-synuclein (α-syn) is the main pathologic event in Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-Syn-seeded fibril formation and its induced toxicity occupy a major role in PD pathogenesis. Thus, assessing compounds that inhibit this seeding process is considered a key towards the therapeutics of synucleinopathies. Using biophysical and biochemical techniques and seeding-dependent cell viability assays, we screened a total of nine natural compounds of alkaloid origin extracted from Chinese medicinal herbs. Of these compounds, synephrine, trigonelline, cytisine, harmine, koumine, peimisine, and hupehenine exhibited in vitro inhibition of α-syn-seeded fibril formation. Furthermore, using cell viability assays, six of these compounds inhibited α-syn-seeding-dependent toxicity. These six potent inhibitors of amyloid fibril formation and toxicity caused by the seeding process represent a promising therapeutic strategy for the treatment of PD and other synucleinopathies.

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