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Neurotoxic

An Ultra-sensitive Assay to Measure Oligomer Induced Toxicity in Human Cerebrospinal Fluid

Total Cost €

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EC-Contrib. €

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Partnership

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 Neurotoxic project word cloud

Explore the words cloud of the Neurotoxic project. It provides you a very rough idea of what is the project "Neurotoxic" about.

monitor    oligomers    proteins    understand    synthetic    membrane    liposome    toxicity    mechanism    concentrations    consistent    unregulated    channels    damage    pathologies    fluorogenic    cerebrospinal    parkinson    neurodegenerative    beta    suitable    exact    compare    prevent    inside    composition    function    sheet    sensitive    influx    binding    ultra    aggregation    native    oligomer    alzheimer    effect    molecule    diseases    synuclein    fibrils    species    technique    unknown    sensor    play    disrupt    patients    protein    cytotoxic    individual    disease    diagnosis    concentration    observation    initiation    containing    structures    single    human    soluble    insights    antibodies    treatment    ion    cytotoxicity    cell    aggregates    neuronal    small    ad    quantify    amyloid    controls    time    monomeric    csf    membranes    pd    toxic    fluid    tau    misfolded    alpha    picomolar    assay    cells    death    progression    healthy    ca2    prp   

Project "Neurotoxic" 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]
 Project website https://ec.europa.eu/programmes/horizon2020/en/h2020-section/marie-sklodowska-curie-actions
 Total cost 195˙454 €
 EC max contribution 195˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2015
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2016
 Duration (year-month-day) from 2016-08-01   to  2018-07-31

 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 195˙454.00

Map

 Project objective

The study of protein aggregates and how they damage neuronal cells is important in order to understand the initiation and progression of several neurodegenerative diseases - including Alzheimer’s disease (AD), Parkinson’s disease (PD). The aggregation from the native monomeric proteins to beta sheet containing amyloid structures involves the formation of different species - misfolded proteins, small soluble oligomers and finally formation of fibrils. It is believed that small oligomers are the most cytotoxic species which play a major role in neuronal loss and cell death. Although, the exact mechanism and extent of amyloid oligomer’s cytotoxicity is still unknown, one of the most consistent pathologies in neurodegenerative disease is unregulated influx of Ca2 into the cell. Individual oligomers directly disrupt cell membranes through non-specific binding at picomolar concentrations leading to the formation of ion channels, which allow Ca2 influx and can lead to cell death. Based on this observation, we will develop a single liposome assay to quantify the oligomer induced toxicity from oligomers present in human cerebrospinal fluid (CSF) from healthy controls and patients with AD and PD. Using a Ca2 sensitive fluorogenic sensor, we will monitor the oligomer induced Ca2 influx inside the liposome in real time. We will measure and compare the toxicity of synthetic oligomers of amyloid beta, alpha-synuclein, tau and PrP oligomers as a function of oligomer concentration and liposome membrane composition. We will then quantify the effect of various antibodies commonly used for treatment of AD and PD on the toxicity of synthetic oligomers and those in CSF. This novel ultra-sensitive state-of-the-art single molecule technique will provide new insights into the mechanism of oligomer induced toxicity, allowing us to identify the most toxic oligomers and the most suitable antibodies to prevent oligomer induced damage as well as having potential for early disease diagnosis.

 Publications

year authors and title journal last update
List of publications.
2018 Franziska Kundel, Suman De, Patrick Flagmeier, Mathew H. Horrocks, Magnus Kjaergaard, Sarah L. Shammas, Sophie E. Jackson, Christopher M. Dobson, David Klenerman
Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity
published pages: , ISSN: 1554-8929, DOI: 10.1021/acschembio.7b01039
ACS Chemical Biology 2019-07-25
2017 Patrick Flagmeier, Suman De, David C. Wirthensohn, Steven F. Lee, Cécile Vincke, Serge Muyldermans, Tuomas P. J. Knowles, Sonia Gandhi, Christopher M. Dobson, David Klenerman
Ultrasensitive Measurement of Ca 2+ Influx into Lipid Vesicles Induced by Protein Aggregates
published pages: 7750-7754, ISSN: 1433-7851, DOI: 10.1002/anie.201700966
Angewandte Chemie International Edition 56/27 2019-07-25
2018 Juan Alberto Varela, Margarida Rodrigues, Suman De, Patrick Flagmeier, Sonia Gandhi, Christopher M. Dobson, David Klenerman, Steven Lee
Optical structural analysis of individual α-synuclein oligomers
published pages: , ISSN: 1433-7851, DOI: 10.1002/anie.201710779
Angewandte Chemie International Edition 2019-07-25
2018 Daniel R. Whiten, Yukun Zuo, Laura Calo, Minee-Liane Choi, Suman De, Patrick Flagmeier, David C. Wirthensohn, Franziska Kundel, Rohan T. Ranasinghe, Santiago E. Sanchez, Dilan Athauda, Steven F. Lee, Christopher M. Dobson, Sonia Gandhi, Maria-Grazia Spillantini, David Klenerman, Mathew H. Horrocks
Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells
published pages: 2033-2038, ISSN: 1439-4227, DOI: 10.1002/cbic.201800209
ChemBioChem 19/19 2019-07-25
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 2019-07-25
2018 Marija Iljina, Alexander J. Dear, Gonzalo A. Garcia, Suman De, Laura Tosatto, Patrick Flagmeier, Daniel R. Whiten, Thomas C. T. Michaels, Daan Frenkel, Christopher M. Dobson, Tuomas P. J. Knowles, David Klenerman
Quantifying Co-Oligomer Formation by α-Synuclein
published pages: , ISSN: 1936-0851, DOI: 10.1021/acsnano.8b03575
ACS Nano 2019-07-25

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