scholarly journals Heme minimizes Parkinson’s disease-associated toxicity by inducing a conformational distortion in the oligomers of alpha-Synuclein

2019 ◽  
Author(s):  
Ritobrita Chakraborty ◽  
Sandip Dey ◽  
Simanta Sarani Paul ◽  
Pallabi Sil ◽  
Jayati Sengupta ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intrinsically Disordered Protein ◽  
Alpha Synuclein ◽  
Oligomeric State ◽  
Intrinsically Disordered ◽  
Nmr Study ◽  
Novel Strategy ◽  
Structural Architecture ◽  
Β Sheet

AbstractAggregation of the intrinsically disordered protein alpha-Synuclein (α-Syn) into insoluble fibrils with a cross-β sheet amyloid structure plays a key role in the neuronal pathology of Parkinson’s disease (PD). The fibrillation pathway of α-Syn encompasses a multitude of transient oligomeric forms differing in size, secondary structure, hydrophobic exposure and toxicity. According to a recent solid state NMR study, the fibrillating unit of α-Syn contains the core residues of the protein arranged into in-register parallel β sheets with a unique Greek key topology. Here, we have shown that the physiologically available small molecule heme (hemin chloride) when added at sub-stoichiometric ratios to either monomeric or aggregated α-Syn, arrests its aggregation in an oligomeric state, which is minimally toxic. Using cryo-EM, we observed that these heme-induced oligomers are ‘mace’-shaped and consist of approximately four monomers. However, the presence of a crucial twist or contortion in their Greek key structural architecture prevents further hierarchical appending into annular oligomers and protofilament formation. We confirm using a His50Gln mutant that the binding of heme onto His50 is crucial in inflicting the structural distortion and is responsible for the stabilization of the non-toxic and off-pathway α-Syn oligomers. We believe that this study provides a novel strategy of developing a therapeutic solution of PD, which has been elusive so far.

scholarly journals Structural basis of synaptic vesicle assembly promoted by α-synuclein

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Giuliana Fusco ◽  
Tillmann Pape ◽  
Amberley D. Stephens ◽  
Pierre Mahou ◽  
Ana Rita Costa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Lewy Bodies ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Familial Parkinson’S Disease

Abstractα-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson’s disease. Although the specific function of αS is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type αS and two mutational variants linked to familial Parkinson’s disease to describe the structural basis of a molecular mechanism enabling αS to induce the clustering of synaptic vesicles. We provide support for this ‘double-anchor’ mechanism by rationally designing and experimentally testing a further mutational variant of αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.

scholarly journals The Interaction of Alpha-synuclein with Membranes and its Implication in Parkinson's Disease: A Literature Review

2015 ◽  
Vol 10 (10) ◽  
pp. 1934578X1501001
Author(s):  
Azucena Gonzalez-Horta
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Membrane Structure ◽  
Intrinsically Disordered Proteins ◽  
Alpha Synuclein ◽  
Disordered Proteins ◽  
Physiological Conditions ◽  
Intrinsically Disordered ◽  
Fluorescence Techniques ◽  
Folded Structure

Alpha-synuclein belongs to the class of intrinsically disordered proteins lacking a well-folded structure under physiological conditions. The conversion of alpha-synuclein from a soluble monomer to an insoluble fibril may underlie the neurodegeneration associated with Parkinson's disease (PD). Although the exact mechanism of alpha-synuclein toxicity is still unknown, it has been proposed that alpha-synuclein disturbs membrane structure, leading to increased membrane permeability and eventual cell death. This review highlights the significant role played by fluorescence techniques in unraveling the nature of interactions between alpha-synuclein and membranes and its implications in PD.

scholarly journals Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium

2020 ◽  
Author(s):  
George R. Nahass ◽  
Yuanzi Sun ◽  
Yong Xu ◽  
Mark Batchelor ◽  
Madeleine Reilly ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Fibrils ◽  
Disease Patient ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Major Constituent ◽  
List Type ◽  
Natural Polyphenol ◽  
Β Sheet

ABSTRACTAlpha-synuclein (α-syn) fibrils, a major constituent of the neurotoxic Lewy Bodies in Parkinson’s disease, form via nucleation dependent polymerization and can replicate by a seeding mechanism. Brazilin, a small molecule derived from red cedarwood trees in Brazil, has been shown to inhibit the fibrillogenesis of amyloid-beta (Aβ) and α-syn, prompting our inquiry in its mechanism of action. Here we test the effects of Brazilin on both seeded and unseeded α-syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of α-syn by a unique mechanism that is distinct from other polyphenols and is also distinct from its effect on Aβ. Brazilin preserves the natively unfolded state of α-syn by stabilizing the compact conformation of the α-syn monomer over the aggregation-competent extended conformation. Molecular docking of Brazilin shows the molecule to interact both with unfolded α-syn monomers and with the cross-β sheet structure of α-syn fibrils. Brazilin eliminates seeding competence of α-syn assemblies from Parkinson’s disease patient brain tissue, and treatment of pre-formed fibril assemblies with Brazilin significantly reduces their toxicity in primary neurons. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson’s Disease.Highlights- The natural polyphenol Brazilin binds to monomeric, oligomeric and fibrillar α-syn- Brazilin shifts the equilibrium away from aggregation-competent monomer conformations- Brazilin inactivates seeding-competent α-syn isolated from Parkinson patients’ brains- Brazilin detoxifies α-syn aggregation intermediates and stabilizes mature amyloid fibrilsGraphical Abstract

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