scholarly journals Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation

2020 ◽  
Author(s):  
Tien M. Phan ◽  
Jeremy D. Schmit
Keyword(s):  
Phase Transitions ◽  
Neurodegenerative Disorders ◽  
Protein Concentration ◽  
Amyloid Fibrils ◽  
Amyloid Aggregation ◽  
Binary Variable ◽  
Conformational Disorder ◽  
Binding Surface ◽  
Elongation Phase ◽  
Degree Of Order

The formation of amyloid fibrils in Alzheimer’s disease and other neurodegenerative disorders is limited by a slow nucleation step due to the entropic cost to initiate the ordered cross-β structure. While the barrier can be lowered if the molecules maintain conformational disorder, poorly ordered clusters provide a poor binding surface for new molecules. To understand these opposing factors, we used all-atom simulations to parameterize a lattice model that treats each amino acid as a binary variable with β-sheet and non-β states. We find that the optimal degree of order in a nucleus depends on protein concentration. Low concentration systems require more ordered nuclei to capture infrequent monomer attachments. The nucleation phase transitions to the elongation phase when the β-sheet core becomes large enough to overcome the initiation cost, at which point further ordering becomes favorable and the nascent fibril efficiently captures new molecules.

scholarly journals Concentration-dependent polymorphism of insulin amyloid fibrils

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8208 ◽  
Author(s):  
Andrius Sakalauskas ◽  
Mantas Ziaunys ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disorders ◽  
Protein Concentration ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Drug Research ◽  
Amyloid Proteins ◽  
Disease Mechanisms ◽  
Slow Progress ◽  
Self Replication

Protein aggregation into highly structured fibrils has long been associated with several neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease. Polymorphism of amyloid fibrils increases the complexity of disease mechanisms and may be one of the reasons for the slow progress in drug research. Here we report protein concentration as another factor leading to polymorphism of insulin amyloid fibrils. Moreover, our data suggests that insulin amyloid conformation can self-replicate only via elongation, while seed-induced nucleation will lead to environment-defined conformation of fibrils. As similar observations were already described for a couple of other amyloid proteins, we suggest it to be a generic mechanism for self-replication of different amyloid fibril conformations.

scholarly journals Exploring the potential of deep-blue autofluorescence for monitoring amyloid fibril formation and dissociation

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7554
Author(s):  
Mantas Ziaunys ◽  
Tomas Sneideris ◽  
Vytautas Smirnovas
Keyword(s):  
Neurodegenerative Disorders ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Fibril Formation ◽  
Amyloid Formation ◽  
Amyloid Aggregation ◽  
Deep Blue ◽  
Amyloid Fibril Formation ◽  
Kinetics Of ◽  
Kinetics Of Fibril Formation

Protein aggregation into amyloid fibrils has been linked to multiple neurodegenerative disorders. Determining the kinetics of fibril formation, as well as their structural stability are important for the mechanistic understanding of amyloid aggregation. Tracking both fibril association and dissociation is usually performed by measuring light scattering of the solution or fluorescence of amyloid specific dyes, such as thioflavin-T. A possible addition to these methods is the recently discovered deep-blue autofluorescence (dbAF), which is linked to amyloid formation. In this work we explore the potential of this phenomenon to monitor amyloid fibril formation and dissociation, as well as show its possible relation to fibril size rather than amyloid structure.

Effects ofin vivoconditions on amyloid aggregation

2019 ◽  
Vol 48 (14) ◽  
pp. 3946-3996 ◽  
Author(s):  
Michael C. Owen ◽  
David Gnutt ◽  
Mimi Gao ◽  
Sebastian K. T. S. Wärmländer ◽  
Jüri Jarvet ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Amyloid Aggregation ◽  
Comprehensive Overview ◽  
Grand Challenges ◽  
Biophysical Chemistry

One of the grand challenges of biophysical chemistry is to understand the principles that govern protein aggregation leading to amyloid fibrils, which is a highly complex and sensitive process. This review provides a comprehensive overview of how amyloid aggregation is affected by the variousin vivoconstituents and conditions.

scholarly journals Catechins as Tools to Understand the Molecular Basis of Neurodegeneration

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3571
Author(s):  
Karla Martinez Pomier ◽  
Rashik Ahmed ◽  
Giuseppe Melacini
Keyword(s):  
Phenolic Compounds ◽  
Neurodegenerative Disorders ◽  
Molecular Basis ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Amyloid Aggregation ◽  
Amyloid Aggregates ◽  
Parkinson’S Diseases ◽  
Pharmacokinetic Properties ◽  
Self Association

Protein misfolding as well as the subsequent self-association and deposition of amyloid aggregates is implicated in the progression of several neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Modulators of amyloidogenic aggregation serve as essential tools to dissect the underlying molecular mechanisms and may offer insight on potential therapeutic solutions. These modulators include green tea catechins, which are potent inhibitors of amyloid aggregation. Although catechins often exhibit poor pharmacokinetic properties and bioavailability, they are still essential tools for identifying the drivers of amyloid aggregation and for developing other aggregation modulators through structural mimicry. As an illustration of such strategies, here we review how catechins have been used to map the toxic surfaces of oligomeric amyloid-like species and develop catechin-based phenolic compounds with enhanced anti-amyloid activity.

Coupling of the lactone-ring conformation with crystal symmetry in 6-hydroxy-4,4,5,7,8-pentamethyl-3,4-dihydrocoumarin

2001 ◽  
Vol 58 (1) ◽  
pp. 125-133 ◽  
Author(s):  
Armand Budzianowski ◽  
Andrzej Katrusiak
Keyword(s):  
Crystal Structure ◽  
Phase Transitions ◽  
Molecular Conformation ◽  
Lactone Ring ◽  
Structural Transformations ◽  
Unit Cell ◽  
Crystal Symmetry ◽  
Translational Symmetry ◽  
Ring Conformation ◽  
Conformational Disorder

Conformational disorder and inversions of the lactone ring induce structural transformations in the crystals of 6-hydroxy-4,4,5,7,8-pentamethyl-3,4-dihydrocoumarin, C14H18O3. The onset of ordering of the lactone ring at 300 K proceeds continuously, changes the space group from P21/m to P21/c and doubles the unit cell; the abrupt inversion of the lactone rings at 225 K changes the crystal translational symmetry in the (010) plane. The mechanism combining the molecular conformation and dynamics with the crystal structure, its symmetry, and phase transitions is presented.

scholarly journals Lysozyme Fibrils Alter the Mechanism of Insulin Amyloid Aggregation

2021 ◽  
Vol 22 (4) ◽  
pp. 1775
Author(s):  
Mantas Ziaunys ◽  
Andrius Sakalauskas ◽  
Tomas Sneideris ◽  
Vytautas Smirnovas
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Protein Aggregates ◽  
Amyloid Aggregation ◽  
Amyloid Aggregates ◽  
Affected Tissue ◽  
New Ideas

Protein aggregation into amyloid fibrils is linked to multiple disorders. The understanding of how natively non-harmful proteins convert to these highly cytotoxic amyloid aggregates is still not sufficient, with new ideas and hypotheses being presented each year. Recently it has been shown that more than one type of protein aggregates may co-exist in the affected tissue of patients suffering from amyloid-related disorders, sparking the idea that amyloid aggregates formed by one protein may induce another protein’s fibrillization. In this work, we examine the effect that lysozyme fibrils have on insulin amyloid aggregation. We show that not only do lysozyme fibrils affect insulin nucleation, but they also alter the mechanism of its aggregation.

An Aβ42 variant that inhibits intra- and extracellular amyloid aggregation and enhances cell viability

2018 ◽  
Vol 475 (19) ◽  
pp. 3087-3103 ◽  
Author(s):  
Ofek Oren ◽  
Victor Banerjee ◽  
Ran Taube ◽  
Niv Papo
Keyword(s):  
Amyloid Fibrils ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Peptide ◽  
Cell Cytotoxicity ◽  
Amyloid Aggregation ◽  
Molar Ratios

Aggregation and accumulation of the 42-residue amyloid β peptide (Aβ42) in the extracellular matrix and within neuronal cells is considered a major cause of neuronal cell cytotoxicity and death in Alzheimer's disease (AD) patients. Therefore, molecules that bind to Aβ42 and prevent its aggregation are therapeutically promising as AD treatment. Here, we show that a non-self-aggregating Aβ42 variant carrying two surface mutations, F19S and L34P (Aβ42DM), inhibits wild-type Aβ42 aggregation and significantly reduces Aβ42-mediated cell cytotoxicity. In addition, Aβ42DM inhibits the uptake and internalization of extracellularly added pre-formed Aβ42 aggregates into cells. This was the case in both neuronal and non-neuronal cells co-expressing Aβ42 and Aβ42DM or following pre-treatment of cells with extracellular soluble forms of the two peptides, even at high Aβ42 to Aβ42DM molar ratios. In cells, Aβ42DM associates with Aβ42, while in vitro, the two soluble recombinant peptides exhibit nano-molar binding affinity. Importantly, Aβ42DM potently suppresses Aβ42 amyloid aggregation in vitro, as demonstrated by thioflavin T fluorescence and transmission electron microscopy for detecting amyloid fibrils. Overall, we present a new approach for inhibiting Aβ42 fibril formation both within and outside cells. Accordingly, Aβ42DM should be evaluated in vivo for potential use as a therapeutic lead for treating AD.

scholarly journals Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8043 ◽  
Author(s):  
Pablo Gracia ◽  
José D. Camino ◽  
Laura Volpicelli-Daley ◽  
Nunilo Cremades
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Disorders ◽  
Lewy Body ◽  
Lewy Body Dementia ◽  
Therapeutic Interventions ◽  
Amyloid Aggregation ◽  
Intermediate Species ◽  
Molecular Feature ◽  
Nucleation Mechanisms ◽  
Disease Specific

α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer’s disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms and dominated by different secondary processes giving rise to multiple amyloid polymorphs and intermediate species. Some aggregated species have more inherent abilities to induce cellular stress and toxicity, while others seem to be more potent in propagating neurodegeneration. The preference for particular types of polymorphs depends on the solution conditions and the cellular microenvironment that the protein encounters, which is likely related to the distinct cellular locations of α-synuclein inclusions in different synucleinopathies, and the existence of disease-specific amyloid polymorphs. In this review, we discuss our current understanding on the nature and structure of the various types of α-synuclein aggregated species and their possible roles in pathology. Precisely defining these distinct α-synuclein species will contribute to understanding the molecular origins of these disorders, developing accurate diagnoses, and designing effective therapeutic interventions for these highly debilitating neurodegenerative diseases.

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