Oligomeric species arising during the aggregation of α-synuclein are implicated as a major source of toxicity in Parkinson's disease, and thus a major potential drug target. However, both their mechanism of formation and role in aggregation are largely unresolved. Here we show that, at physiological pH and in the absence of lipid membranes, α-synuclein aggregates form by secondary nucleation, rather than simple primary nucleation, and that this process is enhanced by agitation.
View Article and Find Full Text PDFFunctional amyloids formed by the protein FapC in bacteria are key structural components of biofilms, which mediate chronic infections and also contribute to antimicrobial resistance. Here, we combine kinetic experiments with mechanistic modelling to probe the role of surfaces in FapC functional amyloid formation. We find that nucleation of new fibrils is predominantly heterogeneous , being catalysed by reaction vessel walls but not by the air/water interface.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
June 2024
Shear forces affect self-assembly processes ranging from crystallization to fiber formation. Here, the effect of mild agitation on amyloid fibril formation was explored for four peptides and investigated in detail for A[Formula: see text]42, which is associated with Alzheimer's disease. To gain mechanistic insights into the effect of mild agitation, nonseeded and seeded aggregation reactions were set up at various peptide concentrations with and without an inhibitor.
View Article and Find Full Text PDFOligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Their lifetime in solution and abundance, governed by the balance of their sources and sinks, are thus important determinants of disease. While significant advances have been made in elucidating the processes that govern oligomer production, the mechanisms behind their dissociation are still poorly understood.
View Article and Find Full Text PDFThe central hallmark of Parkinson's disease pathology is the aggregation of the α-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomeric α-synuclein is relatively stable , but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context of α-synuclein aggregation, their detailed mechanistic role in this process has not been established to date.
View Article and Find Full Text PDFACS Chem Neurosci
December 2022
The self-assembly of the amyloid β 42 (Aβ42) peptide is linked to Alzheimer's disease, and oligomeric intermediates are linked to neuronal cell death during the pathology of the disease. These oligomers are produced prolifically during secondary nucleation, by which the aggregation of monomers is catalyzed on fibril surfaces. Significant progress has been made in understanding the aggregation mechanism of Aβ42; still, a detailed molecular-level understanding of secondary nucleation is lacking.
View Article and Find Full Text PDFThe pathology of Alzheimer's disease is connected to the aggregation of β-amyloid (Aβ) peptide, which exists as a number of length-variants. Truncations and extensions are found at both the N- and C-termini, relative to the most commonly studied 40- and 42-residue alloforms. Here, we investigate the aggregation of two physiologically abundant alloforms, Aβ and Aβ, as pure peptides and in mixtures with Aβ and Aβ.
View Article and Find Full Text PDFThe self-assembly of peptides and proteins into amyloid fibrils plays a causative role in a wide range of increasingly common and currently incurable diseases. The molecular mechanisms underlying this process have recently been discovered, prompting the development of drugs that inhibit specific reaction steps as possible treatments for some of these disorders. A crucial part of treatment design is to determine how much drug to give and when to give it, informed by its efficacy and intrinsic toxicity.
View Article and Find Full Text PDFKnowledge of the mechanisms of assembly of amyloid proteins into aggregates is of central importance in building an understanding of neurodegenerative disease. Given that oligomeric intermediates formed during the aggregation reaction are believed to be the major toxic species, methods to track such intermediates are clearly needed. Here we present a method, electron paramagnetic resonance (EPR), by which the amount of intermediates can be measured over the course of the aggregation, directly in the reacting solution, without the need for separation.
View Article and Find Full Text PDFSelf-assembling peptide-based hydrogels are a class of tunable soft materials that have been shown to be highly useful for a number of biomedical applications. The dynamic formation of the supramolecular fibrils that compose these materials has heretofore remained poorly characterized. A better understanding of this process would provide important insights into the behavior of these systems and could aid in the rational design of new peptide hydrogels.
View Article and Find Full Text PDFThe misfolding and aberrant aggregation of proteins into fibrillar structures is a key factor in some of the most prevalent human diseases, including diabetes and dementia. Low molecular weight oligomers are thought to be a central factor in the pathology of these diseases, as well as critical intermediates in the fibril formation process, and as such have received much recent attention. Moreover, on-pathway oligomeric intermediates are potential targets for therapeutic strategies aimed at interrupting the fibril formation process.
View Article and Find Full Text PDFThe aggregation of peptides and proteins into amyloid fibrils is a molecular self-assembly phenomenon associated with both biological function and malfunction, notably in the context of neurodegenerative diseases. Oligomeric species formed early in the aggregation process are generally associated with cytotoxicity. Extrinsic molecules such as peptides have been found to influence amyloid formation kinetics and regulate this cellular process.
View Article and Find Full Text PDFThe formation of amyloid deposits in human tissues is a defining feature of more than 50 medical disorders, including Alzheimer's disease. Strong genetic and histological evidence links these conditions to the process of protein aggregation, yet it has remained challenging to identify a definitive connection between aggregation and pathogenicity. Using time-resolved fluorescence microscopy of individual synthetic vesicles, we show for the Aβ42 peptide implicated in Alzheimer's disease that the disruption of lipid bilayers correlates linearly with the time course of the levels of transient oligomers generated through secondary nucleation.
View Article and Find Full Text PDFThe spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored.
View Article and Find Full Text PDFAn amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDFOligomeric species 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 that combines 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 found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils.
View Article and Find Full Text PDFThe formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking.
View Article and Find Full Text PDFWe use perturbative renormalization group theory to study the kinetics of protein aggregation phenomena in a unified manner across multiple timescales. Using this approach, we find that, irrespective of the specific molecular details or experimental conditions, filamentous assembly systems display universal behavior in time. Moreover, we show that the universality classes for protein aggregation correspond to simple autocatalytic processes and that the diversity of behavior in these systems is determined solely by the reaction order for secondary nucleation with respect to the protein concentration, which labels all possible universality classes.
View Article and Find Full Text PDFThe aggregation of the prion protein (PrP) plays a key role in the development of prion diseases. In the past decade, a similar process has been associated with other proteins, such as Aβ, tau, and α-synuclein, which participate in other neurodegenerative diseases. It is increasingly recognized that the small oligomeric species of aggregates can play an important role in the development of prion diseases.
View Article and Find Full Text PDFSilk fibroin is a natural protein obtained from the Bombyx mori silkworm. In addition to being the key structural component in silkworm cocoons, it also has the propensity to self-assemble in vitro into hierarchical structures with desirable properties such as high levels of mechanical strength and robustness. Furthermore, it is an appealing biopolymer due to its biocompatability, low immunogenicity, and lack of toxicity, making it a prime candidate for biomedical material applications.
View Article and Find Full Text PDFSmall oligomers of the protein α-synuclein (αS) are highly cytotoxic species associated with Parkinson's disease (PD). In addition, αS can form co-aggregates with its mutational variants and with other proteins such as amyloid-β (Aβ) and tau, which are implicated in Alzheimer's disease. The processes of self-oligomerization and co-oligomerization of αS are, however, challenging to study quantitatively.
View Article and Find Full Text PDFThe misfolding and aggregation of proteins into linear fibrils is widespread in human biology, for example, in connection with amyloid formation and the pathology of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The oligomeric species that are formed in the early stages of protein aggregation are of great interest, having been linked with the cellular toxicity associated with these conditions. However, these species are not characterized in any detail experimentally, and their properties are not well understood.
View Article and Find Full Text PDFACS Chem Neurosci
December 2018
The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these species is prerequisite for a detailed quantitative understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers.
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