scholarly journals Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles

2021 ◽  
Vol 118 (36) ◽  
pp. e2104148118
Author(s):  
Nadejda Koloteva-Levine ◽  
Liam D. Aubrey ◽  
Ricardo Marchante ◽  
Tracey J. Purton ◽  
Jennifer R. Hiscock ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Full Range ◽  
Amyloid Formation ◽  
Surface Activities ◽  
Wide Range ◽  
Experimental Approaches ◽  
The Cross ◽  
Aβ42 Peptide ◽  
Misfolding Diseases ◽  
Amyloid Assembly

Amyloid seeds are nanometer-sized protein particles that accelerate amyloid assembly as well as propagate and transmit the amyloid protein conformation associated with a wide range of protein misfolding diseases. However, seeded amyloid growth through templated elongation at fibril ends cannot explain the full range of molecular behaviors observed during cross-seeded formation of amyloid by heterologous seeds. Here, we demonstrate that amyloid seeds can accelerate amyloid formation via a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds. This type of seeding mechanism is demonstrated through quantitative characterization of the cross-seeded assembly reactions involving two nonhomologous and unrelated proteins: the human Aβ42 peptide and the yeast prion–forming protein Sup35NM. Our results demonstrate experimental approaches to differentiate seeding by templated elongation from nontemplated amyloid seeding and rationalize the molecular mechanism of the cross-seeding phenomenon as a manifestation of the aberrant surface activities presented by amyloid seeds as nanoparticles.

scholarly journals Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles

2020 ◽  
Author(s):  
Nadejda Koloteva-Levine ◽  
Ricardo Marchante ◽  
Tracey J. Purton ◽  
Jennifer R. Hiscock ◽  
Mick F. Tuite ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Full Range ◽  
Amyloid Formation ◽  
Surface Activities ◽  
Wide Range ◽  
Quantitative Characterisation ◽  
The Cross ◽  
Aβ42 Peptide ◽  
Misfolding Diseases ◽  
Amyloid Assembly

ABSTRACTAmyloid seeds are nanometre-sized protein particles that accelerate amyloid assembly, as well as propagate and transmit the amyloid protein conformation associated with a wide range of protein misfolding diseases. However, seeded amyloid growth through templated elongation at fibril ends cannot explain the full range of molecular behaviours observed during cross-seeded formation of amyloid by heterologous seeds. Here, we demonstrate that amyloid seeds can accelerate amyloid formation via a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds. This type of seeding mechanism is demonstrated through quantitative characterisation of the cross-seeded assembly reactions involving two non-homologous and unrelated proteins: the human Aβ42 peptide and the yeast prion-forming protein Sup35NM. Our results suggest experimental approaches to differentiate seeding by templated elongation from non-templated amyloid seeding, and rationalise the molecular mechanism of the cross-seeding phenomenon as a manifestation of the aberrant surface activities presented by amyloid seeds as nanoparticles.

scholarly journals α-Synuclein promotes IAPP fibril formation in vitro and β-cell amyloid formation in vivo in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Marija Mucibabic ◽  
Pär Steneberg ◽  
Emmelie Lidh ◽  
Jurate Straseviciene ◽  
Agnieszka Ziolkowska ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Alpha Synuclein ◽  
Fibril Formation ◽  
Amyloid Formation ◽  
Β Cells ◽  
Β Cell ◽  
Islet Amyloid ◽  
Misfolding Diseases

AbstractType 2 diabetes (T2D), alike Parkinson’s disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in β-cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (αSyn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in β-cells. Here we show that αSyn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, αSyn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of αSyn in hIAPPtg mice enhanced β-cell amyloid formation in vivo whereas β-cell amyloid formation was reduced in hIAPPtg mice on a Snca −/− background. Taken together, our findings provide evidence that αSyn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for αSyn in β-cell amyloid formation.

scholarly journals Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide

2020 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
Andela Šarić ◽  
Samo Curk ◽  
Katja Bernfur ◽  
Paolo Arosio ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Fibril Formation ◽  
Therapeutic Interventions ◽  
Molecular Pathways ◽  
Amyloid Fibril Formation ◽  
Aβ42 Peptide ◽  
Heterogeneous Ensemble ◽  
Misfolding Diseases

AbstractOligomeric aggregates populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer’s disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach combining theory, experiment, and simulation, we reveal in molecular detail the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we find that most Aβ42 oligomers dissociate to their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar species. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.

scholarly journals Modulation of amyloid assembly by glycosaminoglycans: from mechanism to biological significance

2017 ◽  
Vol 95 (3) ◽  
pp. 329-337 ◽  
Author(s):  
Noé Quittot ◽  
Mathew Sebastiao ◽  
Steve Bourgault
Keyword(s):  
Self Assembly ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Biological Significance ◽  
Active Research ◽  
Living Organisms ◽  
Functional Amyloids ◽  
Almost All ◽  
Misfolding Diseases ◽  
Amyloid Assembly

Glycosaminoglycans (GAGs) are long and unbranched polysaccharides that are abundant in the extracellular matrix and basement membrane of multicellular organisms. These linear polyanionic macromolecules are involved in many physiological functions from cell adhesion to cellular signaling. Interestingly, amyloid fibrils extracted from patients afflicted with protein misfolding diseases are virtually always associated with GAGs. Amyloid fibrils are highly organized nanostructures that have been historically associated with pathological states, such as Alzheimer’s disease and systemic amyloidoses. However, recent studies have identified functional amyloids that accomplish crucial physiological roles in almost all living organisms, from bacteria to insects and mammals. Over the last 2 decades, numerous reports have revealed that sulfated GAGs accelerate and (or) promote the self-assembly of a large diversity of proteins, both inherently amyloidogenic and non-aggregation prone. Despite the fact that many studies have investigated the molecular mechanism(s) by which GAGs induce amyloid assembly, the mechanistic elucidation of GAG-mediated amyloidogenesis still remains the subject of active research. In this review, we expose the contribution of GAGs in amyloid assembly, and we discuss the pathophysiological and functional significance of GAG-mediated fibrillization. Finally, we propose mechanistic models of the unique and potent ability of sulfated GAGs to hasten amyloid fibril formation.

scholarly journals Kinetic analysis reveals the rates and mechanisms of protein aggregation in a multicellular organism

2020 ◽  
Author(s):  
Tessa Sinnige ◽  
Georg Meisl ◽  
Thomas C. T. Michaels ◽  
Michele Vendruscolo ◽  
Tuomas P.J. Knowles ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Molecular Model ◽  
Kinetic Studies ◽  
Living Organism ◽  
Model Systems ◽  
Amyloid Formation ◽  
Wide Range

AbstractThe accumulation of insoluble protein aggregates containing amyloid fibrils has been observed in many different human protein misfolding diseases1,2, and their pathological features have been recapitulated in diverse model systems3. In vitro kinetic studies have provided a quantitative understanding of how the fundamental molecular level processes of nucleation and growth lead to amyloid formation4. However, it is not yet clear to what extent these basic biophysical processes translate to amyloid formation in vivo, given the complexity of the cellular and organismal environment. Here we show that the aggregation of a fluorescently tagged polyglutamine (polyQ) protein into µm-sized inclusions in the muscle tissue of living C. elegans can be quantitatively described by a molecular model where stochastic nucleation occurs independently in each cell, followed by rapid aggregate growth. Global fitting of the image-based aggregation kinetics reveals a nucleation rate corresponding to 0.01 h-1 per cell at 1 mM intracellular protein concentration, and shows that the intrinsic stochasticity of nucleation accounts for a significant fraction of the observed animal-to-animal variation. Our results are consistent with observations for the aggregation of polyQ proteins in vitro5 and in cell culture6, and highlight how nucleation events control the overall progression of aggregation in the organism through the spatial confinement into individual cells. The key finding that the biophysical principles associated with protein aggregation in small volumes remain the governing factors, even in the complex environment of a living organism, will be critical for the interpretation of in vivo data from a wide range of protein aggregation diseases.

The Major Transitions in Evolution

1997 ◽  
Author(s):  
John Maynard Smith ◽  
Eors Szathmary
Keyword(s):  
Full Range ◽  
Evolution Of Cooperation ◽  
Major Transitions ◽  
Insect Societies ◽  
Wide Range ◽  
Major Transition ◽  
Life Itself ◽  
History Of ◽  
Emergence Of Cooperation ◽  
Multicellular Organisms

Over the history of life there have been several major changes in the way genetic information is organized and transmitted from one generation to the next. These transitions include the origin of life itself, the first eukaryotic cells, reproduction by sexual means, the appearance of multicellular plants and animals, the emergence of cooperation and of animal societies, and the unique language ability of humans. This ambitious book provides the first unified discussion of the full range of these transitions. The authors highlight the similarities between different transitions--between the union of replicating molecules to form chromosomes and of cells to form multicellular organisms, for example--and show how understanding one transition sheds light on others. They trace a common theme throughout the history of evolution: after a major transition some entities lose the ability to replicate independently, becoming able to reproduce only as part of a larger whole. The authors investigate this pattern and why selection between entities at a lower level does not disrupt selection at more complex levels. Their explanation encompasses a compelling theory of the evolution of cooperation at all levels of complexity. Engagingly written and filled with numerous illustrations, this book can be read with enjoyment by anyone with an undergraduate training in biology. It is ideal for advanced discussion groups on evolution and includes accessible discussions of a wide range of topics, from molecular biology and linguistics to insect societies.

Oxford Studies in Medieval Philosophy Volume 7

2019 ◽  
Keyword(s):  
Late Antiquity ◽  
Full Range ◽  
Current Work ◽  
Medieval Philosophy ◽  
Original Essays ◽  
Wide Range ◽  
Extended Review

Oxford Studies in Medieval Philosophy annually collects the best current work in the field of medieval philosophy. The various volumes print original essays, reviews, critical discussions, and editions of texts. The aim is to contribute to an understanding of the full range of themes and problems in all aspects of the field, from late antiquity into the Renaissance, and extending over the Jewish, Islamic, and Christian traditions. Volume 6 includes work on a wide range of topics, including Davlat Dadikhuda on Avicenna, Christopher Martin on Abelard’s ontology, Jeremy Skrzypek and Gloria Frost on Aquinas’s ontology, Jean‐Luc Solère on instrumental causality, Peter John Hartman on Durand of St.‐Pourçain, and Kamil Majcherek on Chatton’s rejection of final causality. The volume also includes an extended review of Thomas Williams of a new book on Aquinas’s ethics by Colleen McCluskey.

scholarly journals Unusual case of amyloidosis presenting as a jejunal mass

2021 ◽  
Vol 14 (5) ◽  
pp. e240226
Author(s):  
Sachin Mohan ◽  
Elliot Graziano ◽  
James Campbell ◽  
Irshad H Jafri
Keyword(s):  
Small Intestine ◽  
Light Chain ◽  
Protein Misfolding ◽  
Unusual Case ◽  
Gi Tract ◽  
Organ Systems ◽  
Light Chain Disease ◽  
Wide Range ◽  
Amyloid Light Chain ◽  
Possible Cause

Amyloidosis constitutes a heterogeneous group of disorders of protein misfolding that can involve different organ systems. The disease can occur either in a systemic or localised manner that is well known to involve the gastrointestinal (GI) tract. GI amyloidosis can present with a wide range of symptoms including diarrhoea, bleeding and obstruction. This case illustrates a patient with localised jejunal amyloid light chain disease that was diagnosed serendipitously during a workup for haematuria. Our patient was otherwise asymptomatic, but this case underscores the importance of considering amyloidosis as a possible cause of isolated masses of the small intestine.

scholarly journals Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Aβ42 oligomers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Simone Ruggeri ◽  
Johnny Habchi ◽  
Sean Chia ◽  
Robert I. Horne ◽  
Michele Vendruscolo ◽  
...  
Keyword(s):  
Small Molecules ◽  
Single Molecule ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Chemical Sensitivity ◽  
Incomplete Knowledge ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitor ◽  
Misfolding Diseases

AbstractSignificant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer’s and Parkinson’s diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer’s disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases.

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