A5027438059- Alzheimer's disease research and treatments
- Protein Structure and Dynamics
- Prion Diseases and Protein Misfolding
- Supramolecular Self-Assembly in Materials
- Enzyme Structure and Function
- Neuroscience and Neuropharmacology Research
- Genetics, Bioinformatics, and Biomedical Research
- Lipid Membrane Structure and Behavior
- Biomedical and Engineering Education
- Neuroinflammation and Neurodegeneration Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Advanced Neuroimaging Techniques and Applications
- Advanced Electron Microscopy Techniques and Applications
- Amino Acid Enzymes and Metabolism
- Trace Elements in Health
- Cellular transport and secretion
- Neurological diseases and metabolism
- Biotechnology and Related Fields
- Glycosylation and Glycoproteins Research
- Advanced MRI Techniques and Applications
- Microtubule and mitosis dynamics
- Graph theory and applications
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Protein Interaction Studies and Fluorescence Analysis
University of Sussex
2016-2025
Yobe State University
2024
University of Toronto
2022
Rosalind Franklin Institute
2022
Diamond Light Source
2022
National Institute of Allergy and Infectious Diseases
2016
National Institutes of Health
2014-2016
East Sussex County Council
2014
University of Warwick
2009
University of Birmingham
2009
Amyloid-like fibrous crystals formed by the peptide KFFEAAAKKFFE have been previously characterized and provide an ideal model system to examine importance of specific interactions introducing substitutions. We find that removal any phenylalanine residue completely abrogates assembly ability, while charged residues modulate within structure resulting in alternative fibrillar morphologies. X-ray fiber diffraction analysis reveals essential backbone packing molecules is maintained, small...
Abstract Amyloid β1-42 (Aβ1-42) plays a central role in Alzheimer’s disease. The link between structure, assembly and neuronal toxicity of this peptide is major current interest but still poorly defined. Here, we explored relationship by rationally designing variant form Aβ1-42 (vAβ1-42) differing only two amino acids. Unlike Aβ1-42, found that the does not self-assemble, nor it toxic to cells. Moreover, while oligomers impact on synaptic function, vAβ1-42 not. In living animal model system...
β-amyloid 1-42 (Aβ1-42) is a self-assembling peptide that goes through many conformational and morphological changes before forming the fibrils are deposited in extracellular plaques characteristic of Alzheimer's disease. The link between Aβ1-42 structure toxicity major interest, particular, neurotoxic potential oligomeric species. Many studies utilise reversed (Aβ42-1) scrambled (AβS) forms amyloid-β as control peptides. Here, using circular dichroism, thioflavin T fluorescence transmission...
Abstract Misfolding and aggregation of proteins is strongly linked to several neurodegenerative diseases, but how such species bring about their cytotoxic actions remains poorly understood. Here we used specifically-designed optical reporter probes live fluorescence imaging in primary hippocampal neurons characterise the mechanism by which prefibrillar, oligomeric forms Alzheimer’s-associated peptide, Aβ42, exert detrimental effects. We a pH-sensitive reporter, Aβ42-CypHer, track Aβ...
Amyloid fibrils found in plaques Alzheimer's disease (AD) brains are composed of amyloid-β peptides. Oligomeric 1-42 (Aβ42) is thought to play a critical role neurodegeneration AD. Here, we determine how size and conformation affect neurotoxicity internalisation Aβ42 assemblies using biophysical methods, immunoblotting, toxicity assays live-cell imaging. We report significant cytotoxicity oligomers their into neurons. In contrast, show reduced no toxicity. Sonicating generates species...
Abstract Tau undergoes fibrillogenesis in a group of neurodegenerative diseases termed tauopathies. Each tauopathy is characterized by tau fibrils with disease-specific conformations, highlighting the complexity self-assembly. This has led to debate surrounding precise mechanisms that govern self-assembly disease, especially involvement disulphide bonding (DSB) between cysteine residues. In this study, we use truncated form tau, dGAE, capable forming filaments identical those disease. We...
An expression and mutagenesis system for the E. coli Class II fructose-1,6-bisphosphate aldolase has been created by modification of vector pKfda (Biochem. J. 257 (1989) 529-534). Large amounts (about 1 g/l in crude extracts), with properties consistent those previously reported naturally occurring enzyme 169 (1978) 633-641) are obtained. The contains 2 zinc ions per dimer. We have investigated nature zinc-binding site site-directed mutagenesis. His-108, His-111, Cys-112 His-142 were...
Flow linear dichroism (LD) spectroscopy provides information on the orientation of molecules in solution and hence relative parts molecules. Long such as fibrous proteins can be aligned Couette flow cells characterized using LD. We have measured calculated from first principles LD representing prototypical secondary structure classes: a self-assembling fiber tropomyosin (all-α-helical), FtsZ (an αβ protein), an amyloid fibril (β-sheet), collagen [poly(proline)II helices]. The combination...
Protein misfolding is common to neurodegenerative diseases (NDs) including Alzheimer's disease (AD), which partly characterized by the self-assembly and accumulation of amyloid-beta in brain. Lysosomes are a critical component proteostasis network required degrade recycle material from outside within cell impaired proteostatic mechanisms have been implicated NDs. We previously established that toxic oligomers endocytosed, accumulate lysosomes, disrupt endo-lysosomal system neurons. Here, we...
Assembly of tau protein into paired helical filaments and straight is a key feature Alzheimer's disease. Aggregation has been implicated in neurodegeneration, cellular toxicity the propagation, which accompanies disease progression. We have reported previously that region (297-391), referred to as dGAE, assembles spontaneously physiological conditions form filament-like fibres vitro absence additives such heparin. This provides valuable tool with explore effects cell culture. Here we studied...
A characteristic hallmark of Alzheimer's Disease (AD) is the pathological aggregation and deposition tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs). Oxidative stress an early event during AD pathogenesis associated with tau-mediated pathology. environments can result formation covalent dityrosine crosslinks that increase protein stability insolubility. Dityrosine cross-linking has been shown Aβ plaques α-synuclein aggregates Lewy bodies ex vivo tissue sections,...
ABSTRACT Glycosylphosphatidylinositol (GPI) anchoring of the prion protein (PrP C ) influences PrP misfolding into disease-associated isoform, res , as well propagation and infectivity. GPI proteins are found in cholesterol- sphingolipid-rich membrane regions called rafts. Exchanging anchor for a nonraft transmembrane sequence redirects away from Previous studies showed that variants resist conversion to when transfected scrapie-infected N2a neuroblastoma cells, likely due segregation...
Alzheimer's disease is linked to increased levels of amyloid beta (Aβ) in the brain, but mechanisms underlying neuronal dysfunction and neurodegeneration remain enigmatic. Here, we investigate whether organizational characteristics functional presynaptic vesicle pools, key determinants information transmission central nervous system, are targets for elevated Aβ. Using an optical readout method cultured hippocampal neurons, show that acute Aβ42 treatment significantly enlarges fraction...
Abstract The tau protein (residues 297-391) forms the core of oligomers and filaments that drive neurodegeneration in Alzheimer’s disease (AD). mechanisms pathological assembly pharmacological inhibition need to be understood before novel treatments can developed. Molecular dynamics modeling, confirmed by immunochemistry, revealed self-assembly involves initial capture via residues 337-355 a conformational switch at proline 332, followed unfolding zipper-like into stable H-bonded structure...
Various proteins and peptides are able to self assemble into amyloid fibrils that associated with disease. Structural characterisation of these fibres is limited by their insoluble heterogeneous nature. However, advances in various techniques including X-ray diffraction, cryo-electron microscopy solid state NMR have provided detailed information on fibrils, from the long range order macromolecular structure atomic interactions promote assembly stabilise core. The cross-β model has been...
The ability to assemble form β-sheet rich fibrils in vitro is shared by a broad range of precursor proteins and peptides. ordered aggregation deposition number specific polypeptides are associated with diseases including Alzheimer's disease Diabetes type 2 recently it has been shown that the highly stable nature amyloid exploited organisms as functional materials. Here we describe capacity peptides various different structures, each sharing amyloid-like structure, but differing arrangements...
Tau35 is a truncated form of tau found in human brain subset tauopathies. expression mice recapitulates key features disease, including progressive increase phosphorylation, along with cognitive and motor dysfunction. The appearance aggregated suggests that may have structural properties distinct from those other species could account for its pathological role disease. To address this hypothesis, we performed characterization monomeric compared the results to two longer isoforms, 2N3R 2N4R...