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Full-Text Articles in Social and Behavioral Sciences
Clusterin Facilitates In Vivo Clearance Of Extracellular Misfolded Proteins, Amy R. Wyatt, Justin J. Yerbury, Paula Berghofer, I Greguric, Andrew Katsifis, Christopher Dobson, Mark R. Wilson
Clusterin Facilitates In Vivo Clearance Of Extracellular Misfolded Proteins, Amy R. Wyatt, Justin J. Yerbury, Paula Berghofer, I Greguric, Andrew Katsifis, Christopher Dobson, Mark R. Wilson
Mark R Wilson
The extracellular deposition of misfolded proteins is a characteristic of many debilitating age-related disorders. However, little is known about the specific mechanisms that act to suppress this process in vivo. Clusterin (CLU) is an extracellular chaperone that forms stable and soluble complexes with misfolded client proteins. Here we explore the fate of complexes formed between CLU and misfolded proteins both in vitro and in a living organism. We show that proteins injected into rats are cleared more rapidly from circulation when complexed with CLU as a result of their more efficient localisation to the liver and that this clearance is …
Potential Roles Of Abundant Extracellular Chaperones In The Control Of Amyloid Formation And Toxicity, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Potential Roles Of Abundant Extracellular Chaperones In The Control Of Amyloid Formation And Toxicity, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Mark R Wilson
The in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors …
Extracellular Chaperones Modulate The Effects Of Alzheimer's Patient Cerebrospinal Fluid On A Beta(1-42) Toxicity And Uptake , Justin J. Yerbury, Mark R. Wilson
Extracellular Chaperones Modulate The Effects Of Alzheimer's Patient Cerebrospinal Fluid On A Beta(1-42) Toxicity And Uptake , Justin J. Yerbury, Mark R. Wilson
Mark R Wilson
Alzheimer's disease is characterised by the inappropriate death of brain cells and accumulation of the A beta peptide in the brain. Thus, it is possible that there are fundamental differences between Alzheimer's disease patients and healthy individuals in their abilities to clear A beta from brain fluid and to protect neurons from A beta toxicity. In the present study, we examined (1) the cytotoxicity of Alzheimer's disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer's disease and control CSF to protect cells from A beta toxicity and to promote cell-mediated clearance of A beta and lastly …
Extracellular Chaperones And Amyloids, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Extracellular Chaperones And Amyloids, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Mark R Wilson
The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to …
Identification Of Human Plasma Proteins As Major Clients For The Extracellular Chaperone Clusterin, Amy R. Wyatt, Mark R. Wilson
Identification Of Human Plasma Proteins As Major Clients For The Extracellular Chaperone Clusterin, Amy R. Wyatt, Mark R. Wilson
Mark R Wilson
Clusterin (CLU) is an extracellular chaperone that is likely to play an important role in protein folding quality control. This study identified three deposition disease-associated proteins as major plasma clients for clusterin by studying CLU-client complexes formed in response to physiologically relevant stress (shear stress, similar to 36 dynes/cm(2) at 37 degrees C). Analysis of plasma samples by size exclusion chromatography indicated that (i) relative to control plasma, stressed plasma contained proportionally more soluble protein species of high molecular weight, and (ii) high molecular weight species were far more abundant when proteins purified by anti-CLU immunoaffinity chromatography from stressed plasma …
Therapeutic Targets In Extracellular Protein Deposition Diseases, Amy R. Wyatt, Justin J. Yerbury, Stephen Poon, Mark R. Wilson
Therapeutic Targets In Extracellular Protein Deposition Diseases, Amy R. Wyatt, Justin J. Yerbury, Stephen Poon, Mark R. Wilson
Mark R Wilson
Many litres of fluids are found outside cells in the human body. These fluids are rich in dissolved proteins that each have a characteristic three dimensional shape, necessary for normal function, which has been attained by the correct folding of their polypeptide chain(s). The structure of these extracellular proteins can be damaged by a variety of environmental stresses (e. g. heat and oxidation) leading to their partial unfolding and aggregation. This in turn can produce toxic soluble aggregates and/or large insoluble protein deposits, either of which can disrupt normal body function (e. g. in Alzheimer's disease and the systemic amyloidoses). …
The Extracellular Chaperone Clusterin Sequesters Oligomeric Forms Of The Amyloid-Beta 1-40 Peptide, Priyanka Narayan, Angel Orte, Richard Clarke, Benedetta Bolognesi, Sharon Hook, Kristina Ganzinger, Sarah Meehan, Mark Wilson, Christopher Dobson, David Klenerman
The Extracellular Chaperone Clusterin Sequesters Oligomeric Forms Of The Amyloid-Beta 1-40 Peptide, Priyanka Narayan, Angel Orte, Richard Clarke, Benedetta Bolognesi, Sharon Hook, Kristina Ganzinger, Sarah Meehan, Mark Wilson, Christopher Dobson, David Klenerman
Mark R Wilson
In recent genome-wide association studies, the extracellular chaperone protein, clusterin, has been identified as a newly-discovered risk factor in Alzheimer's disease. We have examined the interactions between human clusterin and the Alzheimer's disease-associated amyloid-β 1-40 peptide (Aβ 1-40), which is prone to aggregate into an ensemble of oligomeric intermediates implicated in both the proliferation of amyloid fibrils and in neuronal toxicity. Using highly sensitive single-molecule fluorescence methods, we have found that Aβ 1-40 forms a heterogeneous distribution of small oligomers (from dimers to 50-mers), all of which interact with clusterin to form long-lived, stable complexes. Consequently, clusterin is able to …
Amyloid-Β Oligomers Are Sequestered By Both Intracellular And Extracellular Chaperones, P Narayan, Sarah Meehan, John Carver, Mark Wilson, C M Dobson, D Klenerman
Amyloid-Β Oligomers Are Sequestered By Both Intracellular And Extracellular Chaperones, P Narayan, Sarah Meehan, John Carver, Mark Wilson, C M Dobson, D Klenerman
Mark R Wilson
The aberrant aggregation of the amyloid-β peptide into β-sheet rich, fibrillar structures proceeds via a heterogeneous ensemble of oligomeric intermediates that have been associated with neurotoxicity in Alzheimer’s disease (AD). Of particular interest in this context are the mechanisms by which molecular chaperones, part of the primary biological defenses against protein misfolding, influence Aβ aggregation. We have used single-molecule fluorescence techniques to compare the interactions between distinct aggregation states (monomers, oligomers, and amyloid fibrils) of the AD-associated amyloid-β(1–40) peptide, and two molecular chaperones, both of which are upregulated in the brains of patients with AD and have been found colocalized …
The Chaperone Action Of Clusterin And Its Putative Role In Quality Control Of Extracellular Protein Folding, Amy Wyatt, Justin Yerbury, Stephen Poon, Rebecca Dabbs, Mark Wilson
The Chaperone Action Of Clusterin And Its Putative Role In Quality Control Of Extracellular Protein Folding, Amy Wyatt, Justin Yerbury, Stephen Poon, Rebecca Dabbs, Mark Wilson
Mark R Wilson
The function(s) of clusterin may depend upon its topological location. A variety of intracellular "isoforms" of clusterin have been reported but further work is required to better define their identity. The secreted form of clusterin has a potent ability to inhibit both amorphous and amyloid protein aggregation. In the case of amorphous protein aggregation, clusterin forms stable, soluble high-molecular-weight complexes with misfolded client proteins. Clusterin expression is increased during many types of physiological and pathological stresses and is thought to function as an extracellular chaperone (EC). The pathology of a variety of serious human diseases is thought to arise as …
The Extracellular Chaperone Clusterin Influences Amyloid Formation And Toxicity By Interacting With Pre-Fibrillar Structures, Justin Yerbury, Stephen Poon, Sarah Meehan, Brianna Thompson, Janet Kumita, Christopher Dobson, Mark Wilson
The Extracellular Chaperone Clusterin Influences Amyloid Formation And Toxicity By Interacting With Pre-Fibrillar Structures, Justin Yerbury, Stephen Poon, Sarah Meehan, Brianna Thompson, Janet Kumita, Christopher Dobson, Mark Wilson
Mark R Wilson
Clusterin is an extracellular chaperone present in all disease-associated extracellular amyloid deposits, however, its roles in amyloid formation and protein deposition in vivo are poorly understood. The current study initially aimed to characterise the effects of clusterin on amyloid formation in vitro by a panel of eight protein substrates. Two of the substrates (Alzheimer's beta peptide and a PI3-SH3 domain) were then used in further experiments to examine the effects of clusterin on amyloid cytotoxicity and to probe the mechanism of clusterin action. We show that clusterin exerts potent effects on amyloid formation, the nature and extent of which vary …
The Extracellular Chaperone Clusterin Potently Inhibits Human Lysozyme Amyloid Formation By Interacting With Prefibrillar Species, Mark Wilson, Justin Yerbury, Stephen Poon, Christopher Dobson, C V Robinson, Elise Stewart, Janet Kumita, Mireille Dumoulin, Gemma Caddy, Christine Hagan
The Extracellular Chaperone Clusterin Potently Inhibits Human Lysozyme Amyloid Formation By Interacting With Prefibrillar Species, Mark Wilson, Justin Yerbury, Stephen Poon, Christopher Dobson, C V Robinson, Elise Stewart, Janet Kumita, Mireille Dumoulin, Gemma Caddy, Christine Hagan
Mark R Wilson
We have studied the effects of the extracellular molecular chaperone, clusterin, on the in vitro aggregation of mutational variants of human lysozyme, including one associated with familial amyloid disease. The aggregation of the amyloidogenic variant I56T is inhibited significantly at clusterin-to-lysozyme ratios as low as 1:80 (i.e. one clusterin molecule per 80 lysozyme molecules). Experiments indicate that under the conditions where inhibition of aggregation occurs, clusterin does not bind detectably to the native or fibrillar states, or to the monomeric transient intermediate known to be a key species in the aggregation reaction. Rather, it seems to interact with oligomeric species …
Effects Of Glycosylation On The Structure And Function Of The Extracellular Chaperone Clusterin, Elise Stewart, Andrew Aquilina, Simon B Easterbrook-Smith, D Murphy-Durland, C Jacobsen, S Moestrup, Mark Wilson
Effects Of Glycosylation On The Structure And Function Of The Extracellular Chaperone Clusterin, Elise Stewart, Andrew Aquilina, Simon B Easterbrook-Smith, D Murphy-Durland, C Jacobsen, S Moestrup, Mark Wilson
Mark R Wilson
Clusterin is the first well characterized, constitutively secreted extracellular chaperone that binds to exposed regions of hydrophobicity on non-native proteins. It may help control the folding state of extracellular proteins by targeting them for receptor-mediated endocytosis and intracellular lysosomal degradation. A notable feature of secreted clusterin is its heavy glycosylation. Although carbohydrate comprises approximately 20−25% of the total mass of the mature molecule, its function is unknown. Results from the current study demonstrate that deglycosylation of human serum clusterin had little effect on its overall secondary structure content but produced a small increase in solvent-exposed hydrophobicity and enhanced the propensity …
The Acute Phase Protein Haptoglobin Is A Mammalian Extracellular Chaperone With An Action Similar To Clusterin, Justin Yerbury, Mark S Rybchyn, Simon B Easterbrook-Smith, C. Henriques, Mark Wilson
The Acute Phase Protein Haptoglobin Is A Mammalian Extracellular Chaperone With An Action Similar To Clusterin, Justin Yerbury, Mark S Rybchyn, Simon B Easterbrook-Smith, C. Henriques, Mark Wilson
Mark R Wilson
Haptoglobin (Hp) is an acidic glycoprotein present in most body fluids of humans and other mammals. Although the functions of Hp are not yet fully understood, the available evidence indicates that it is likely to play an important role in suppressing inflammatory responses. Some earlier work suggested that Hp might be a newly identified member of a small group of extracellular chaperones found at significant levels in human body fluids. Previously, the only well-characterized member of this group was clusterin, which shares functional similarities with the small heat-shock proteins. We report here that Hp specifically inhibited the precipitation of a …