scholarly journals Origin, Toxicity and Characteristics of Two Amyloid Oligomer Polymorphs

2021 ◽  
Author(s):  
Chamani Niyangoda ◽  
Jeremy Barton ◽  
Nabila Bushra ◽  
Kanchana Karunarathne ◽  
Grahama Strauss ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Compelling Evidence ◽  
Significant Progress ◽  
Amyloid Diseases ◽  
Amyloid Oligomer

There is compelling evidence that small oligomeric aggregates, emerging during the assembly of amyloid fibrils and plaques, are important molecular pathogens in many amyloid diseases. While significant progress has been...

The discovery and development of transthyretin amyloidogenesis inhibitors: what are the lessons?

2021 ◽  
Author(s):  
Bin Zhong ◽  
Xianhua Huang ◽  
Yizhou Zheng ◽  
Xiaohua Guo ◽  
Longhuo Wu
Keyword(s):  
Crown Ethers ◽  
Binding Sites ◽  
Amyloid Fibrils ◽  
Review Article ◽  
Therapeutic Management ◽  
Binding Modes ◽  
Therapeutic Approaches ◽  
Amyloid Diseases

Transthyretin (TTR) is associated with several human amyloid diseases. Various kinetic stabilizers have been developed to inhibit the dissociation of TTR tetramer and the formation of amyloid fibrils. Most of them are bisaryl derivatives, natural flavonoids, crown ethers and carborans. In this review article we focus on TTR tetramer stabilizers, genetic therapeutic approaches and fibril remodelers. The binding modes of typical bisaryl derivatives, natural flavonoids, crown ethers and carborans are discussed. Based on knowledge of the binding of thyroxine to TTR tetramer, many stabilizers have been screened to dock into the thyroxine binding sites, leading to TTR tetramer stabilization. Particularly, those stabilizers with unique binding profiles have shown great potential in developing the therapeutic management of TTR amyloidogenesis.

scholarly journals Structural Studies of the Amyloid State of Proteins

2014 ◽  
Vol 70 (a1) ◽  
pp. C797-C797
Author(s):  
David Eisenberg ◽  
Arthur Laganowsky ◽  
Cong Liu ◽  
Michael Sawaya ◽  
Julian Whitelegge ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Protein Sequences ◽  
Beta Sheets ◽  
Structural Studies ◽  
Amyloid Fibers ◽  
X Ray ◽  
Amyloid Oligomers ◽  
Oligomeric Complex ◽  
Amyloid Diseases ◽  
Short Protein

Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. At the morphological level, these fibers appear similar and are termed "amyloid." We found that the adhesive segments of amyloid fibers are short protein sequences which form pairs of interdigitated, in-register beta sheets. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that in the neurodegenerative diseases, smaller, often transient and polymorphic oligomers are the toxic entities. We have identified a segment of the amyloid-forming protein, alphaB crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: beta-sheet-rich structure, cytotoxicity, and recognition by an anti-oligomer antibody. The X-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six anti-parallel, out-of-register protein strands, which we term a cylindrin. The cylindrin structure is compatible with sequence segments from the Abeta protein of Alzheimer's disease and from other amyloid proteins. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers, and are distinct in structure from amyloid fibrils.

scholarly journals Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition

2018 ◽  
Vol 115 (29) ◽  
pp. E6741-E6750 ◽  
Author(s):  
Lorena Saelices ◽  
Kevin Chung ◽  
Ji H. Lee ◽  
Whitaker Cohn ◽  
Julian P. Whitelegge ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Ex Vivo ◽  
Standard Of Care ◽  
Wild Type ◽  
Current Standard ◽  
Transthyretin Amyloidosis ◽  
Physiological Conditions ◽  
Type Gene ◽  
Amyloid Diseases

Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutantTTRgene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.

scholarly journals Transthyretin microheterogeneity and molecular interactions: implications for amyloid formation

2014 ◽  
Vol 5 (3) ◽  
pp. 257-264
Author(s):  
Michael Landreh ◽  
Linus J. Östberg ◽  
Tom M. Pettersson ◽  
Hans Jörnvall
Keyword(s):  
Amyloid Fibrils ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Amyloid Formation ◽  
Rate Limiting Step ◽  
Pharmacological Prevention ◽  
Dietary Components ◽  
Rate Limiting ◽  
Amyloid Diseases ◽  
Tetrameric Form

AbstractAggregation of transthyretin (TTR), a plasma-binding protein for thyroxine and retinol-binding protein, is the cause of several amyloid diseases. Disease-associated mutations are well known, but wild-type TTR is, to a lesser extent, also amyloidogenic. Monomerization, not oligomer formation as in several other depository diseases, is the rate-limiting step in TTR aggregation, and stabilization of the natively tetrameric form can inhibit amyloid formation. Modifications on Cys10, as well as interactions with native ligands in plasma, were early found to influence the equilibrium between tetrameric and monomeric TTR by dissociating or stabilizing the tetramer. Following these discoveries, synthetic ligands for pharmacological prevention of TTR aggregation could be developed. In this article, we outline how the different types of TTR interactions and its microheterogeneity in plasma are related to its propensity to form amyloid fibrils. We conclude that plasma constituents and dietary components may act as natural TTR stabilizers whose mechanisms of action provide cues for the amelioration of TTR amyloid disease.

scholarly journals Formation and participation of nano-amyloids in pathogenesis of Alzheimer's disease and other amyloidogenic diseases

2010 ◽  
Vol 56 (6) ◽  
pp. 624-638 ◽  
Author(s):  
A.V. Maltsev ◽  
O.V. Galzitskaya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Beta Amyloid ◽  
Conformational Transitions ◽  
Native Conformation ◽  
The World ◽  
Triggering Mechanisms ◽  
Amyloid Diseases

Studies of neurodegenetrative disorders have become particularly actual attracting the attention of researchers from over the world because of the dissemination of Alzheimer's disease. The reason for such pathogenesis is the transition of a "healthy" molecule or peptide from the native conformation into a very stable "pathological" isoform. During this, molecules in the "pathological" conformation aggregate, forming amyloid fibrils that can increase without any control. Novel knowledge is required on sporadic isoforms of Alzheimer's disease, on the nature of triggering mechanisms of conformational transitions of beta-amyloid fragments from normally functioning proteins into new formations - nano-beta-amyloids - that spiral out of control of neurons and organism which leads to the loss of neurons. Herein we review studies devoted to the formation of amyloid fibrils and their role in pathogenesis of amyloid diseases.

scholarly journals Identification of two principal amyloid-driving segments in variable domains of Ig light chains in AL amyloidosis

2018 ◽  
Author(s):  
Boris Brumshtein ◽  
Shannon R. Esswein ◽  
Michael R. Sawaya ◽  
Alan T. Ly ◽  
Meytal Landau ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Experimental Approach ◽  
Amyloid Fibril ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chains ◽  
Monoclonal Immunoglobulin ◽  
Variable Domains ◽  
Β Sheets ◽  
Amyloid Diseases

ABSTRACTSystemic light chain amyloidosis (AL) is a disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into β-sheets that pair forming a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, we identify segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate there are at least two such segments. Each one can drive amyloid fibril assembly independently of the other. Thus these two segments are therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach to identify segments that drive fibril formation in other amyloid diseases.

scholarly journals Unraveling the Complexity of Amyloid Polymorphism Using Gold Nanoparticles and Cryo-EM

2019 ◽  
Author(s):  
Urszula Cendrowska ◽  
Paulo Jacob Silva ◽  
Nadine Ait-Bouziad ◽  
Marie Müller ◽  
Zekiye Pelin Guven ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Light Chain ◽  
Human Tissue ◽  
Amyloid Fibrils ◽  
Disease Patient ◽  
Structural Basis ◽  
Al Amyloidosis ◽  
Amyloid Diseases

AbstractThe misfolding and self-assembly of proteins into β-sheet-rich amyloid fibrils of various structures and morphologies is a hallmark of several neurodegenerative and systemic diseases. Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicity and pathology-spreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report on the use of 11-mercapto-1-undecanesulfonate-coated gold nanoparticles (NPs) to label the edges of synthetic, recombinant and native amyloid fibrils to assess amyloid morphological polymorphism using cryogenic transmission electron microscopy (cryo-EM). The fibrils studied were derived from amyloid proteins involved in disorders of the central nervous system (amyloid-β, tau, α-synuclein) and in systemic amyloidosis (a fragment of an immunoglobulin λ light chain). The labeling efficiency enabled imaging and characterization of amyloid fibrils of different morphologies under hydrated conditions using cryo-EM. These NPs allowed for the visualization of morphological features that are not directly observed using standard imaging techniques, including TEM with use of the negative stain or cryo-EM imaging. We also demonstrate the use of these NPs to label native paired helical filaments (PHFs) from the postmortem brain of an Alzheimer’s disease patient, as well as amyloid fibrils extracted from the heart tissue of a patient suffering from systemic amyloid light-chain (AL) amyloidosis. Analysis of the cryo-EM images of amyloids decorated with NPs shows exceptional homogeneity across the fibrils derived from human tissue in comparison to fibrils aggregated in vitro. The use of these NPs enabled us to gain novel insight into the structural features that distinguish amyloid fibrils formed in vivo from those formed in cell-free in vitro systems. Our findings demonstrate that these NPs represent a powerful tool for rapid imaging and profiling of amyloid morphological polymorphism in different types of samples, including those derived from complex biological aggregates found in human tissue and animal models of amyloid diseases. These advances should not only facilitate the profiling and characterization of amyloids for structural studies by cryo-EM but also pave the way to elucidate the structural basis of amyloid strains and toxicity and possibly the correlation between the pathological and clinical heterogeneity of amyloid diseases.

scholarly journals Protease Resistance of ex vivo Amyloid Fibrils implies the proteolytic Selection of disease-associated Fibril Morphologies

2021 ◽  
Author(s):  
Jonathan Schoenfelder ◽  
Peter Benedikt Pfeiffer ◽  
Tejaswini Pradhan ◽  
Johan Bijzet ◽  
Bouke P.C. Hazenberg ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Ex Vivo ◽  
Amino Acid Sequences ◽  
The Body ◽  
Amyloid A ◽  
Chain Analysis ◽  
Polypeptide Chains ◽  
Amyloid Diseases ◽  
Selection Of

Several studies recently showed that ex vivo fibrils from patient or animal tissue were structurally different from in vitro formed fibrils from the same polypeptide chain. Analysis of serum amyloid A (SAA) and Aβ-derived amyloid fibrils additionally revealed that ex vivo fibrils were more protease stable than in vitro fibrils. These observations gave rise to the proteolytic selection hypothesis that suggested that disease-associated amyloid fibrils were selected inside the body by their ability to resist endogenous clearance mechanisms. We here show, for more than twenty different fibril samples, that ex vivo fibrils are more protease stable than in vitro fibrils. These data support the idea of a proteolytic selection of pathogenic amyloid fibril morphologies and help to explain why only few amino acid sequences lead to amyloid diseases, although many, if not all, polypeptide chains can form amyloid fibrils in vitro.

Starting at the beginning: endoplasmic reticulum proteostasis and systemic amyloid disease

2020 ◽  
Vol 477 (9) ◽  
pp. 1721-1732
Author(s):  
Isabelle C. Romine ◽  
R. Luke Wiseman
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Amyloid Fibrils ◽  
Therapeutic Potential ◽  
Peripheral Target ◽  
Disease Pathogenesis ◽  
Amyloid Disease ◽  
Amyloidogenic Proteins ◽  
Amyloidogenic Protein ◽  
Amyloid Diseases

Systemic amyloid diseases are characterized by the deposition of an amyloidogenic protein as toxic oligomers and amyloid fibrils on tissues distal from the site of protein synthesis. Traditionally, these diseases have been viewed as disorders of peripheral target tissues where aggregates are deposited, and toxicity is observed. However, recent evidence highlights an important role for endoplasmic reticulum (ER) proteostasis pathways within tissues synthesizing and secreting amyloidogenic proteins, such as the liver, in the pathogenesis of these disorders. Here, we describe the pathologic implications of ER proteostasis and its regulation on the toxic extracellular aggregation of amyloidogenic proteins implicated in systemic amyloid disease pathogenesis. Furthermore, we discuss the therapeutic potential for targeting ER proteostasis to reduce the secretion and toxic aggregation of amyloidogenic proteins to mitigate peripheral amyloid-associated toxicity involved in the onset and progression of systemic amyloid diseases.

scholarly journals Amyloid as a natural product

2003 ◽  
Vol 161 (3) ◽  
pp. 461-462 ◽  
Author(s):  
Jeffery W. Kelly ◽  
William E. Balch
Keyword(s):  
Natural Product ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Integral Membrane Protein ◽  
Fibril Formation ◽  
Proteolytic Processing ◽  
Biological Pathway ◽  
Peptide Fragment ◽  
Amyloid Fibril Formation ◽  
Amyloid Diseases

Amyloid fibrils, such as those found in Alzheimer's and the gelsolin amyloid diseases, result from the misassembly of peptides produced by either normal or aberrant intracellular proteolytic processing. A paper in this issue by Marks and colleagues (Berson et al., 2003) demonstrates that intra-melanosome fibrils are formed through normal biological proteolytic processing of an integral membrane protein. The resulting peptide fragment assembles into fibrils promoting the formation of melanin pigment granules. These results, along with the observation that amyloid fibril formation by bacteria is highly orchestrated, suggest that fibril formation is an evolutionary conserved biological pathway used to generate natural product nanostructures.

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