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Oligomers SIGNED

Characterising protein oligomers and their role in neurodegenerative disease in humans

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EC-Contrib. €

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Project "Oligomers" data sheet

The following table provides information about the project.

Coordinator
THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE 

Organization address
address: TRINITY LANE THE OLD SCHOOLS
city: CAMBRIDGE
postcode: CB2 1TN
website: www.cam.ac.uk

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country United Kingdom [UK]
 Total cost 2˙499˙551 €
 EC max contribution 2˙499˙551 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-ADG
 Funding Scheme ERC-ADG
 Starting year 2015
 Duration (year-month-day) from 2015-09-01   to  2021-08-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    THE CHANCELLOR MASTERS AND SCHOLARSOF THE UNIVERSITY OF CAMBRIDGE UK (CAMBRIDGE) coordinator 2˙499˙551.00

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 Project objective

Small soluble protein aggregates play a key role in the onset and spreading of Alzheimer’s and Parkinson’s diseases. However, which oligomers are present in human disease and which are toxic remains unknown because ultrasensitive methods do not exist to detect and characterise the low concentration of oligomers, which are highly heterogeneous in size and structure. To address this problem we will develop fluorescence based methods to detect and characterise individual oligomers to measure the oligomer size, structure, proteinase K resistance, seeding capability and composition. We will also develop methods to enrich these oligomers so we can use mass spectrometry to determine post translational modifications and recover the oligomers to directly test their cytotoxicity and mechanism of damage. The capability to characterise these oligomers at this unprecedented level of detail will represent a major advance in the field. These methods will then be applied to stem cell models of Alzheimer’s disease and Parkinson’s disease and then clinical samples of CSF from patients. These experiments will determine how the number, composition or structure of the oligomers changes in the disease and if this results in increased cytotoxicity. Clinical samples of CSF from patients with genetic mutations will be used to determine if detectable changes in the oligomers occur early in the disease and samples of brain tissue used to determine the changes in oligomers during the spreading of the disease.

By the end of the project we will have determined which oligomers play major roles in the onset and spreading of Alzheimer’s and Parkinson’s disease in humans, providing targets for therapies, and tested if the detection and characterisation of these oligomers can be used for early diagnosis of the disease.

 Publications

year authors and title journal last update
List of publications.
2019 Suman De, David C. Wirthensohn, Patrick Flagmeier, Craig Hughes, Francesco A. Aprile, Francesco S. Ruggeri, Daniel R. Whiten, Derya Emin, Zengjie Xia, Juan A. Varela, Pietro Sormanni, Franziska Kundel, Tuomas P. J. Knowles, Christopher M. Dobson, Clare Bryant, Michele Vendruscolo, David Klenerman
Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-019-09477-3
Nature Communications 10/1 2020-03-23
2020 Craig Hughes, Minee L. Choi, Jee-Hyun Yi, Seung-Chan Kim, Anna Drews, Peter St. George-Hyslop, Clare Bryant, Sonia Gandhi, Kwangwook Cho, David Klenerman
Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death
published pages: , ISSN: 2399-3642, DOI: 10.1038/s42003-020-0792-9
Communications Biology 3/1 2020-03-23
2019 Suman De, Daniel R. Whiten, Francesco S. Ruggeri, Craig Hughes, Margarida Rodrigues, Dimitrios I. Sideris, Christopher G. Taylor, Francesco A. Aprile, Serge Muyldermans, Tuomas P. J. Knowles, Michele Vendruscolo, Clare Bryant, Kaj Blennow, Ingmar Skoog, Silke Kern, Henrik Zetterberg, David Klenerman
Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer’s disease progression
published pages: , ISSN: 2051-5960, DOI: 10.1186/s40478-019-0777-4
Acta Neuropathologica Communications 7/1 2020-03-23
2019 Craig D. Hughes, Minee L. Choi, Mina Ryten, Lee Hopkins, Anna Drews, Juan A. Botía, Maria Iljina, Margarida Rodrigues, Sarah A. Gagliano, Sonia Gandhi, Clare Bryant, David Klenerman
Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis
published pages: 103-120, ISSN: 0001-6322, DOI: 10.1007/s00401-018-1907-y
Acta Neuropathologica 137/1 2020-03-23
2018 Ji-Eun Lee, Jason C. Sang, Margarida Rodrigues, Alexander R. Carr, Mathew H. Horrocks, Suman De, Marie N. Bongiovanni, Patrick Flagmeier, Christopher M. Dobson, David J. Wales, Steven F. Lee, David Klenerman
Mapping Surface Hydrophobicity of α-Synuclein Oligomers at the Nanoscale
published pages: 7494-7501, ISSN: 1530-6984, DOI: 10.1021/acs.nanolett.8b02916
Nano Letters 18/12 2020-03-23
2018 Mathew Horrocks, Daniel R Whiten, Yukun Zuo, Laura Calo, Minee-Liane Choi, Suman De, Patrick Flagmeier, David C Wirthensohn, Franziska Kundel, Steven F Lee, Christopher Dobson, Sonia Gandhi, Maria Spillantini, David Klenerman, Rohan T Ranasinghe, Santiago E Sanchez, Dilan Athauda
Nanoscopic characterization of individual endogenous protein aggregates in human neuronal cells
published pages: , ISSN: 1439-4227, DOI: 10.1002/cbic.201800209
ChemBioChem 2020-03-03
2018 Christopher G. Taylor, Georg Meisl, Mathew H. Horrocks, Henrik Zetterberg, Tuomas P. J. Knowles, David Klenerman
Extrinsic Amyloid-Binding Dyes for Detection of Individual Protein Aggregates in Solution
published pages: 10385-10393, ISSN: 0003-2700, DOI: 10.1021/acs.analchem.8b02226
Analytical Chemistry 90/17 2020-03-03
2018 Kundel, F.; Hong, L.; Falcon, B.; McEwan, W. A.; Michaels, T. C. T.; Meisl, G.; Esteras, N.; Abramov, A. Y.; Knowles, T. J. P.; Goedert, M.; Klenerman, D.
Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading
published pages: 1276–1282, ISSN: 1948-7193, DOI: 10.17863/CAM.25419
ACS Chemical Neuroscience (2018) 2020-03-03
2018 Daniel R. Whiten, Dezerae Cox, Mathew H. Horrocks, Christopher G. Taylor, Suman De, Patrick Flagmeier, Laura Tosatto, Janet R. Kumita, Heath Ecroyd, Christopher M. Dobson, David Klenerman, Mark R. Wilson
Single-Molecule Characterization of the Interactions between Extracellular Chaperones and Toxic α-Synuclein Oligomers
published pages: 3492-3500, ISSN: 2211-1247, DOI: 10.1016/j.celrep.2018.05.074
Cell Reports 23/12 2020-03-03

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