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540 results on '"Ashcroft, Alison E."'

1. Insights into the consequences of co-polymerisation in the early stages of IAPP and Aβ peptide assembly from mass spectrometry

Author

Young, Lydia M, Mahood, Rachel A, Saunders, Janet C, Tu, Ling-Hsien, Raleigh, Daniel P, Radford, Sheena E, and Ashcroft, Alison E

Subjects
Neurodegenerative, Neurosciences, Brain Disorders, Aging, Alzheimer's Disease, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Metabolic and endocrine, Amino Acid Sequence, Amyloid beta-Peptides, Humans, Islet Amyloid Polypeptide, Molecular Sequence Data, Peptide Fragments, Protein Multimerization, Protein Stability, Protein Structure, Secondary, Spectrometry, Mass, Electrospray Ionization, Analytical Chemistry, Other Chemical Sciences
Abstract

The precise molecular mechanisms by which different peptides and proteins assemble into highly ordered amyloid deposits remain elusive. The fibrillation of human amylin (also known as islet amyloid polypeptide, hIAPP) and the amyloid-beta peptide (Aβ-40) are thought to be pathogenic factors in Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), respectively. Amyloid diseases may involve co-aggregation of different protein species, in addition to the self-assembly of single precursor sequences. Here we investigate the formation of heterogeneous pre-fibrillar, oligomeric species produced by the co-incubation of hIAPP and Aβ-40 using electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS)-based methods. Conformational properties and gas-phase stabilities of amyloid oligomers formed from hIAPP or Aβ40 alone, and from a 1 : 1 mixture of hIAPP and Aβ40 monomers, were determined and compared. We show that co-assembly of the two sequences results in hetero-oligomers with distinct properties and aggregation kinetics properties compared with the homo-oligomers present in solution. The observations may be of key significance to unravelling the mechanisms of amyloid formation in vivo and elucidating how different sequences and/or assembly conditions can result in different fibril structures and/or pathogenic outcomes.

Published
2015

2. Mutational Analysis of the Ability of Resveratrol To Inhibit Amyloid Formation by Islet Amyloid Polypeptide: Critical Evaluation of the Importance of Aromatic–Inhibitor and Histidine–Inhibitor Interactions

Author

Tu, Ling-Hsien, Young, Lydia M, Wong, Amy G, Ashcroft, Alison E, Radford, Sheena E, and Raleigh, Daniel P

Subjects
Complementary and Integrative Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Brain Disorders, Neurodegenerative, Dementia, Aging, Amino Acid Sequence, Amino Acids, Aromatic, Amyloid, Arginine, Benzothiazoles, Catechin, DNA Mutational Analysis, Histidine, Humans, Islet Amyloid Polypeptide, Molecular Sequence Data, Mutant Proteins, Resveratrol, Spectrometry, Mass, Electrospray Ionization, Stilbenes, Structure-Activity Relationship, Thiazoles, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
Abstract

The process of amyloid formation by the normally soluble hormone islet amyloid polypeptide (IAPP) contributes to β-cell death in type 2 diabetes and in islet transplants. There are no clinically approved inhibitors of islet amyloidosis, and the mode of action of existing inhibitors is not well-understood. Resveratrol, a natural polyphenol, has been reported to inhibit amyloid formation by IAPP and by the Alzheimer's disease Aβ peptide. The mechanism of action of this compound is not known, nor is its mode of interaction with IAPP. In this study, we use a series of IAPP variants to examine possible interactions between resveratrol and IAPP. Fluorescence assays, transmission electron microscopy, and mass spectrometry demonstrate that resveratrol is much less effective as an inhibitor of IAPP amyloid formation than the polyphenol (-)-epigallocatechin 3-gallate (EGCG) and, unlike EGCG, does not significantly disaggregate preformed IAPP amyloid fibrils. Resveratrol is also shown to interfere with thioflavin-T assays. His-18 mutants, a truncation mutant, mutants of each of the aromatic residues, and mutants of Arg-11 of IAPP were examined. Mutation of His to Gln or Leu weakens the ability of resveratrol to inhibit amyloid formation by IAPP, as do mutations of Arg-11, Phe-15, or Tyr-37 to Leu, and truncation to form the variant Ac 8-37-IAPP, which removes the first seven residues to eliminate Lys-1 and the N-terminal amino group. In contrast, replacement of Phe-23 with Leu has a smaller effect. The data highlight Phe-15, His-18, and Tyr-37 as being important for IAPP-resveratrol interactions and are consistent with a potential role of the N-terminus and Arg-11 in polypeptide-resveratrol interactions.

Published
2015

3. Screening and classifying small-molecule inhibitors of amyloid formation using ion mobility spectrometry–mass spectrometry

Author

Young, Lydia M, Saunders, Janet C, Mahood, Rachel A, Revill, Charlotte H, Foster, Richard J, Tu, Ling-Hsien, Raleigh, Daniel P, Radford, Sheena E, and Ashcroft, Alison E

Subjects
Analytical Chemistry, Chemical Sciences, Physical Chemistry, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Dementia, Acquired Cognitive Impairment, Aging, Neurodegenerative, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Neurological, Amino Acid Sequence, Amyloid, Amyloid beta-Peptides, Colloids, Humans, Islet Amyloid Polypeptide, Molecular Sequence Data, Peptide Fragments, Protein Binding, Small Molecule Libraries, Spectrometry, Mass, Electrospray Ionization, Organic Chemistry, Chemical sciences
Abstract

The search for therapeutic agents that bind specifically to precursor protein conformations and inhibit amyloid assembly is an important challenge. Identifying such inhibitors is difficult because many protein precursors of aggregation are partially folded or intrinsically disordered, which rules out structure-based design. Furthermore, inhibitors can act by a variety of mechanisms, including specific or nonspecific binding, as well as colloidal inhibition. Here we report a high-throughput method based on ion mobility spectrometry-mass spectrometry (IMS-MS) that is capable of rapidly detecting small molecules that bind to amyloid precursors, identifying the interacting protein species and defining the mode of inhibition. Using this method we have classified a variety of small molecules that are potential inhibitors of human islet amyloid polypeptide (hIAPP) aggregation or amyloid-beta 1-40 aggregation as specific, nonspecific, colloidal or non-interacting. We also demonstrate the ability of IMS-MS to screen for inhibitory small molecules in a 96-well plate format and use this to discover a new inhibitor of hIAPP amyloid assembly.

Published
2015

5. A snapshot of electrified nanodroplets

Author

Arscott, Steve, Descatoire, Cedric, Buchaillot, Lionel, and Ashcroft, Alison E.

Subjects
Physics - Fluid Dynamics, Condensed Matter - Materials Science
Abstract

We investigate the size distribution of electrically charged nanodroplets. The droplets were generated using nano- and micro- scale silicon tips. A brief voltage pulse results in a "snapshot" of charged nanodroplets on a metal surface. Atomic force microscopy (AFM) of the snapshot revealed that certain droplet diameters are favored suggesting droplet fission due to Rayleigh instability at nanometer length scales. The most occurring droplet diameters are 85.9(4.1) nm and 167.1 nm (9.7 nm) and for nano- and micro- scale tips respectively indicating that the tip size determines deposition resolution.

Published
2011
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6. Ion Mobility Spectrometry–Mass Spectrometry Defines the Oligomeric Intermediates in Amylin Amyloid Formation and the Mode of Action of Inhibitors

Author

Young, Lydia M, Cao, Ping, Raleigh, Daniel P, Ashcroft, Alison E, and Radford, Sheena E

Subjects
Autoimmune Disease, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Animals, Humans, Islet Amyloid Polypeptide, Ligands, Rats, Silybin, Silymarin, Small Molecule Libraries, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Chemical Sciences, General Chemistry
Abstract

The molecular mechanisms by which different proteins assemble into highly ordered fibrillar deposits and cause disease remain topics of debate. Human amylin (also known as islet amyloid polypeptide/hIAPP) is found in vivo as amyloid deposits in the pancreatic islets of sufferers of type II diabetes mellitus, and its self-aggregation is thought to be a pathogenic factor in disease and to contribute to the failure of islet transplants. Here, electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) has been used to monitor oligomer formation from IAPP. The detection, identification and characterization of oligomers from both human and rat amylin (rIAPP) are described. Oligomers up to and including hexamers have been detected for both peptides. From ESI-IMS-MS derived collision cross sections (CCS), these species are shown to be elongated in conformation. Collision-induced dissociation (CID-MS/MS) revealed differences in the gas-phase stability of the oligomers formed from hIAPP and rIAPP, which may contribute to their differences in amyloid propensity. Using ESI-IMS-MS, the mode of inhibition of amyloid formation from hIAPP using small molecules or co-incubation with rIAPP was also investigated. We show that the polyphenolic compounds epigallocatechin gallate (EGCG) and silibinin bind to specific conformers within a dynamic ensemble of hIAPP monomers, altering the progress of oligomerization and fibril assembly. Hetero-oligomer formation also occurs with rIAPP but leads only to inefficient inhibition. The results indicate that although different small molecules can be effective inhibitors of hIAPP self-assembly, their modes of action are distinct and can be distinguished using ESI-IMS-MS.

Published
2014

8. Inducing protein aggregation by extensional flow

Author

Dobson, John, Kumar, Amit, Willis, Leon F., Tuma, Roman, Higazi, Daniel R., Turner, Richard, Lowe, David C., Ashcroft, Alison E., Radford, Sheena E., Kapur, Nikil, and Brockwell, David J.

Published
2017

14. Structure, Substrate Recognition, and Mechanism of the Na+-Hydantoin Membrane Transport Protein, Mhp1

Author

Jackson, Scott M., primary, Ivanova, Ekaterina, additional, Calabrese, Antonio N., additional, Polyakova, Anna, additional, Sharples, David J., additional, Shimamura, Tatsuro, additional, Brueckner, Florian, additional, Simmons, Katie J., additional, Sahai, Michelle, additional, Majd, Homa, additional, Kunji, Edmund, additional, Ahmad, Irshad, additional, Weyand, Simone, additional, Suzuki, Shun’ichi, additional, Ashcroft, Alison E., additional, Kokkinidou, Maria, additional, Pearson, Arwen, additional, Beckstein, Oliver, additional, Baldwin, Stephen A., additional, Iwata, So, additional, Cameron, Alexander D., additional, and Henderson, Peter J. F., additional

Published
2019
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17. Structure, Substrate Recognition, and Mechanism of the Na+-Hydantoin Membrane Transport Protein, Mhp1

Author

Jackson, Scott M., primary, Ivanova, Ekaterina, additional, Calabrese, Antonio N., additional, Polyakova, Anna, additional, Sharples, David J., additional, Shimamura, Tatsuro, additional, Brueckner, Florian, additional, Simmons, Katie J., additional, Sahai, Michelle, additional, Majd, Homa, additional, Kunji, Edmund, additional, Ahmad, Irshad, additional, Weyand, Simone, additional, Suzuki, Shun’ichi, additional, Ashcroft, Alison E., additional, Kokkinidou, Maria, additional, Pearson, Arwen, additional, Beckstein, Oliver, additional, Baldwin, Stephen A., additional, Iwata, So, additional, Cameron, Alexander D., additional, and Henderson, Peter J. F., additional

Published
2018
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43. Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo

Author

Dobson, Claire L., Devine, Paul W. A., Phillips, Jonathan J., Higazi, Daniel R., Lloyd, Christopher, Popovic, Bojana, Arnold, Joanne, Buchanan, Andrew, Lewis, Arthur, Goodman, Joanne, van der Walle, Christopher F., Thornton, Peter, Vinall, Lisa, Lowne, David, Aagaard, Anna, Olsson, Lise-Lotte, Ridderstad Wollberg, Anna, Welsh, Fraser, Karamanos, Theodoros K., Pashley, Clare L., Iadanza, Matthew G., Ranson, Neil A., Ashcroft, Alison E., Kippen, Alistair D., Vaughan, Tristan J., Radford, Sheena E., and Lowe, David C.

Published
2016
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