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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 …
Ans Binding Reveals Common Features Of Cytotoxic Amyloid Species, Benedetta Bolognesi, Janet Kumita, Teresa Barros, Elin Esbjorner, Leila Luheshi, Damian Crowther, Mark Wilson, Christopher Dobson, Giorgio Favrin, Justin Yerbury
Ans Binding Reveals Common Features Of Cytotoxic Amyloid Species, Benedetta Bolognesi, Janet Kumita, Teresa Barros, Elin Esbjorner, Leila Luheshi, Damian Crowther, Mark Wilson, Christopher Dobson, Giorgio Favrin, Justin Yerbury
Mark R Wilson
Oligomeric assemblies formed from a variety of disease-associated peptides and proteins have been strongly associated with toxicity in many neurodegenerative conditions, such as Alzheimer's disease. The precise nature of the toxic agents, however, remains still to be established. We show that prefibrillar aggregates of E22G (arctic) variant of the A beta(1-42) peptide bind strongly to 1-anilinonaphthalene 8-sulfonate and that changes in this property correlate significantly with changes in its cytotoxicity. Moreover, we show that this phenomenon is common to other amyloid systems, such as wild-type A beta(1-42), the 159T variant of human lysozyme and an SH3 domain. These findings are …
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 …
Amyloid Fibril Formation By Bovine Milk Kappa-Casein And Its Inhibition By The Molecular Chaperones Alpha-S And Beta-Casein, Mark Wilson, David Thorn, Agata Rekas, S. L Gras, Christopher Dobson, Sarah Meehan, Cait Macphee, M Sunde
Amyloid Fibril Formation By Bovine Milk Kappa-Casein And Its Inhibition By The Molecular Chaperones Alpha-S And Beta-Casein, Mark Wilson, David Thorn, Agata Rekas, S. L Gras, Christopher Dobson, Sarah Meehan, Cait Macphee, M Sunde
Mark R Wilson
No abstract provided.