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Annual Review of Neuroscience 2011Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with... (Review)
Review
Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidogenic Proteins; Animals; Brain; Humans; Models, Biological
PubMed: 21456963
DOI: 10.1146/annurev-neuro-061010-113613 -
Cell Sep 2021The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike... (Review)
Review
The hidden world of amyloid biology has suddenly snapped into atomic-level focus, revealing over 80 amyloid protein fibrils, both pathogenic and functional. Unlike globular proteins, amyloid proteins flatten and stack into unbranched fibrils. Stranger still, a single protein sequence can adopt wildly different two-dimensional conformations, yielding distinct fibril polymorphs. Thus, an amyloid protein may define distinct diseases depending on its conformation. At the heart of this conformational variability lies structural frustrations. In functional amyloids, evolution tunes frustration levels to achieve either stability or sensitivity according to the fibril's biological function, accounting for the vast versatility of the amyloid fibril scaffold.
Topics: Amyloidogenic Proteins; Animals; Disease; Evolution, Molecular; Humans; Polymorphism, Genetic; Protein Folding; Protein Stability
PubMed: 34534463
DOI: 10.1016/j.cell.2021.08.013 -
Molecules (Basel, Switzerland) Mar 2022Most neurodegenerative diseases such as Alzheimer's disease, type 2 diabetes, Parkinson's disease, etc. are caused by inclusions and plaques containing misfolded protein... (Review)
Review
Most neurodegenerative diseases such as Alzheimer's disease, type 2 diabetes, Parkinson's disease, etc. are caused by inclusions and plaques containing misfolded protein aggregates. These protein aggregates are essentially formed by the interactions of either the same (homologous) or different (heterologous) sequences. Several experimental pieces of evidence have revealed the presence of cross-seeding in amyloid proteins, which results in a multicomponent assembly; however, the molecular and structural details remain less explored. Here, we discuss the amyloid proteins and the cross-seeding phenomena in detail. Data suggest that targeting the common epitope of the interacting amyloid proteins may be a better therapeutic option than targeting only one species. We also examine the dual inhibitors that target the amyloid proteins participating in the cross-seeding events. The future scopes and major challenges in understanding the mechanism and developing therapeutics are also considered. Detailed knowledge of the amyloid cross-seeding will stimulate further research in the practical aspects and better designing anti-amyloid therapeutics.
Topics: Amyloid; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Diabetes Mellitus, Type 2; Humans
PubMed: 35335141
DOI: 10.3390/molecules27061776 -
Chemical Reviews Jul 2021This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark of protein misfolding diseases and therefore have... (Review)
Review
This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark of protein misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures have been elucidated from various in vitro and ex vivo obtained fibrils. In parallel, the process of fibril formation has been studied in vitro under highly artificial but comparatively reproducible conditions. The review starts with a summary of what is known and speculated from artificial in vitro amyloid-type protein aggregation experiments. A partially hypothetic fibril selection model will be described that may be suitable to explain why amyloid fibrils look the way they do, in particular, why at least all so far reported high resolution cryo-electron microscopy obtained fibril structures are in register, parallel, cross-β-sheet fibrils that mostly consist of two protofilaments twisted around each other. An intrinsic feature of the model is the prion-like nature of all amyloid assemblies. Transferring the model from the in vitro point of view to the in vivo situation is not straightforward, highly hypothetic, and leaves many open questions that need to be addressed in the future.
Topics: Amyloid; Amyloidogenic Proteins; Animals; Cryoelectron Microscopy; Humans; Prions; Protein Aggregates
PubMed: 34137605
DOI: 10.1021/acs.chemrev.1c00196 -
Current Opinion in Structural Biology Oct 2021Nuclear magnetic resonance (NMR) has long been instrumental in the characterization of intrinsically disordered proteins (IDPs) and intrinsically disordered regions... (Review)
Review
Nuclear magnetic resonance (NMR) has long been instrumental in the characterization of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). This method continues to offer rich insights into the nature of IDPs in solution, especially in combination with other biophysical methods such as small-angle scattering, single-molecule fluorescence, electron paramagnetic resonance (EPR), and mass spectrometry. Substantial advances have been made in recent years in studies of proteins containing both ordered and disordered domains and in the characterization of problematic sequences containing repeated tracts of a single or a few amino acids. These sequences are relevant to disease states such as Alzheimer's, Parkinson's, and Huntington's diseases, where disordered proteins misfold into harmful amyloid. Innovative applications of NMR are providing novel insights into mechanisms of protein aggregation and the complexity of IDP interactions with their targets. As a basis for understanding the solution structural ensembles, dynamic behavior, and functional mechanisms of IDPs and IDRs, NMR continues to prove invaluable.
Topics: Amyloidogenic Proteins; Intrinsically Disordered Proteins; Magnetic Resonance Spectroscopy; Protein Conformation; Scattering, Small Angle
PubMed: 33951592
DOI: 10.1016/j.sbi.2021.03.015 -
The EMBO Journal Aug 2022Although amyloid fibres are highly stable protein aggregates, a specific combination of human Hsp70 system chaperones can disassemble them, including fibres formed of...
Although amyloid fibres are highly stable protein aggregates, a specific combination of human Hsp70 system chaperones can disassemble them, including fibres formed of α-synuclein, huntingtin, or Tau. Disaggregation requires the ATPase activity of the constitutively expressed Hsp70 family member, Hsc70, together with the J domain protein DNAJB1 and the nucleotide exchange factor Apg2. Clustering of Hsc70 on the fibrils appears to be necessary for disassembly. Here we use atomic force microscopy to show that segments of in vitro assembled α-synuclein fibrils are first coated with chaperones and then undergo bursts of rapid, unidirectional disassembly. Cryo-electron tomography and total internal reflection fluorescence microscopy reveal fibrils with regions of densely bound chaperones, preferentially at one end of the fibre. Sub-stoichiometric amounts of Apg2 relative to Hsc70 dramatically increase recruitment of Hsc70 to the fibres, creating localised active zones that then undergo rapid disassembly at a rate of ~ 4 subunits per second. The observed unidirectional bursts of Hsc70 loading and unravelling may be explained by differences between the two ends of the polar fibre structure.
Topics: Amyloid; Amyloidogenic Proteins; HSC70 Heat-Shock Proteins; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Molecular Chaperones; Protein Aggregates; Protein Binding; alpha-Synuclein
PubMed: 35698800
DOI: 10.15252/embj.2021110410 -
Journal of Molecular Biology Oct 2018Biofilms are ubiquitous in the natural and man-made environment. They are defined as microbes that are encapsulated in an extracellular, self-produced, biofilm matrix.... (Review)
Review
Biofilms are ubiquitous in the natural and man-made environment. They are defined as microbes that are encapsulated in an extracellular, self-produced, biofilm matrix. Growing evidence from the genetic and biochemical analysis of single species biofilms has linked the presence of fibrous proteins to a functional biofilm matrix. Some of these fibers have been described as functional amyloid or amyloid-like fibers. Here we provide an overview of the biophysical and biological data for a wide range of protein fibers found in the biofilm matrix of Gram-positive and Gram-negative bacteria.
Topics: Amyloid; Amyloidogenic Proteins; Bacterial Proteins; Biofilms; Biophysical Phenomena; Chemical Phenomena; Disease Susceptibility; Escherichia coli Proteins; Extracellular Polymeric Substance Matrix; Pseudomonas; Solubility; Spectrum Analysis; Structure-Activity Relationship
PubMed: 30098341
DOI: 10.1016/j.jmb.2018.07.026 -
The FEBS Journal Apr 2022Amyloid aggregation results from the self-assembly of identical aggregation-prone sequences into cross-beta-sheet structures. The process is best known for its... (Review)
Review
Amyloid aggregation results from the self-assembly of identical aggregation-prone sequences into cross-beta-sheet structures. The process is best known for its association with a wide range of human pathologies but also as a functional mechanism in all kingdoms of life. Less well elucidated is the role of heterotypic interactions between amyloids and other proteins and macromolecules and how this contributes to disease. We here review current data with a focus on neurodegenerative amyloid-associated diseases. Evidence indicates that heterotypic interactions occur in a wide range of amyloid processes and that these interactions modify fundamental aspects of amyloid aggregation including seeding, aggregation rates and toxicity. More work is required to understand the mechanistic origin of these interactions, but current understanding suggests that both supersaturation and sequence-specific binding can contribute to heterotypic amyloid interactions. Further unravelling these mechanisms may help to answer outstanding questions in the field including the selective vulnerability of cells types and tissues and the stereotypical spreading patterns of amyloids in disease.
Topics: Amyloid; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Humans; Neurodegenerative Diseases
PubMed: 33460517
DOI: 10.1111/febs.15719 -
Applied Microbiology and Biotechnology Dec 2022Microbe (including bacteria, fungi, and virus) infection in brains is associated with amyloid fibril deposit and neurodegeneration. Increasing findings suggest that... (Review)
Review
Microbe (including bacteria, fungi, and virus) infection in brains is associated with amyloid fibril deposit and neurodegeneration. Increasing findings suggest that amyloid proteins, like Abeta (Aβ), are important innate immune effectors in preventing infections. In some previous studies, amyloid peptides have been linked to antimicrobial peptides due to their common mechanisms in membrane-disruption ability, while the other mechanisms of bactericidal protein aggregation and protein function knockdown are less discussed. Besides, another important function of amyloid peptides in pathogen agglutination is rarely illustrated. In this review, we summarized and divided the different roles and mechanisms of amyloid peptides against microbes in antimicrobial activity and microbe agglutination activity. Besides, the range of amyloids' antimicrobial spectrum, the effectiveness of amyloid peptide states (monomers, oligomers, and fibrils), and cytotoxicity are discussed. The good properties of amyloid peptides against microbes might provide implications for the development of novel antimicrobial drug. KEY POINTS: • Antimicrobial and/or microbial agglutination is a characteristic of amyloid peptides. • Various mechanisms of amyloid peptides against microbes are discovered recently. • Amyloid peptides might be developed into novel antimicrobial drugs.
Topics: Amyloid; Amyloid beta-Peptides; Anti-Infective Agents; Amyloidogenic Proteins; Anti-Bacterial Agents; Agglutination
PubMed: 36322251
DOI: 10.1007/s00253-022-12246-w -
Biochemistry. Biokhimiia Dec 2017This review considers data on structural and functional features of titin, on the role of this protein in determination of mechanical properties of sarcomeres, and on... (Review)
Review
This review considers data on structural and functional features of titin, on the role of this protein in determination of mechanical properties of sarcomeres, and on specific features of regulation of the stiffness and elasticity of its molecules, amyloid aggregation of this protein in vitro, and possibilities of formation of intramolecular amyloid structure in vivo. Molecular mechanisms are described of protection of titin against aggregation in muscle cells. Based on the data analysis, it is supposed that titin and the formed by it elastic filaments have features of amyloid.
Topics: Amyloidogenic Proteins; Animals; Connectin; Elasticity; Humans; Sarcomeres
PubMed: 29523065
DOI: 10.1134/S0006297917130077