In vivo mechanisms of neurotoxicity

Lead Research Organisation: MRC Toxicology Unit

Abstract

One of the greatest challenges in neuroscience, and to public health, is how to treat neurodegenerative diseases. These diseases involve the death of brain cells. When they are lost, the functions they control memory, movement and emotion are also irreversibly lost. In order to treat these disorders, we need to understand why brain cells degenerate and die. Most importantly, we need to understand the earliest stages of this process as this gives us the greatest chance of intervening to prevent cell death. I previously made a mouse model of prion disease in which early degeneration is reversible. In these mice, early structural changes in brain cells lead to changes in behaviour, memory and electrical signalling, very like early changes seen in human neurodegenerative disorders. Using either special genetic techniques we were able to reverse this process. The structural, behavioural and memory changes were all reversed and instead of dying, the mice recovered and lived a normal lifespan. We aim to understand the processes that control this recovery and use this to find targets for treating neurodegeneration.

Technical Summary

Neurodegenerative diseases, such as Alzheimers, Parkinsons, Huntingtons disease and amyotrophic lateral sclerosis, have enormous clinical and economic impact world wide. Irrespective of the final pattern of clinical symptoms, they all are caused by an irreversible loss of neurons, which cannot be cured. But before neuronal death, there are neuronal dysfunction and synaptic impairment, which potentially can be treated.||My background is in prion diseases, modelling these in transgenic mice to look at mechanisms of neurotoxicity and developing new therapeutic approaches. In particular, I focused on the changes of early prion neurotoxicity and recovery from it. This new programme uses mouse models to understand the early molecular events in prion and other neurodegenerative diseases, looking in parallel at potential therapeutic targets for prevention of neuronal dysfunction and death.||Our main aims are to:|1. Characterise pre-degenerative neuronal changes.|2. Understand what triggers ultimate commitment to death in a malfunctioning neuron.|3. Define the molecular targets and the temporal window for functional recovery.||Initially, these questions will be addressed using our established mouse model of prion disease where early pathology is associated with a pivotal point in neuronal survival/death, and there is potential for recovery. We will use molecular biological, biochemical and neurophysiological techniques, as well as neuronal imaging in culture and in vivo to characterise the underlying cellular and synaptic changes, including alterations in signalling pathways and ion channels.||The broader aims of the programme are:|4. to generate new mouse models to look at individual pathways implicated in early dysfunction and their effect on neuronal function and death.|5. to address therapeutic strategies for the treatment of neurodegeneration.

Publications


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Bradley SJ (2017) M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. in The Journal of clinical investigation
Brinkmalm A (2014) Targeting synaptic pathology with a novel affinity mass spectrometry approach. in Molecular & cellular proteomics : MCP
Freeman OJ (2016) The UPR and synaptic dysfunction in neurodegeneration. in Brain research
Halliday M (2014) Prions: generation and spread versus neurotoxicity. in The Journal of biological chemistry
 
Description Chair, UK-India Joint Centre Partnerships Panel (MRC-DPT)
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description MRC Neuroscience strategy board
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description Member of MRC Neuroscience and Mental Health Board
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description RSM clinical neuroscience council
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guidance committee
 
Description leicester neuroscience steering committee
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guidance committee
 
Description Alz Soc/ADDF Drug repuprosing
Amount £200,000 (GBP)
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2015 
End 02/2017
 
Description ERC consolidator award
Amount € 2,000,000 (EUR)
Funding ID UPR-­Neuro 647479 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 09/2015 
End 08/2020
 
Description MRC
Amount £250,000 (GBP)
Funding ID RG79399 
Organisation MRC-UK 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2015 
End 01/2018
 
Description MRC intramural programme funding
Amount £2,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Toxicology Unit
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2013 
End 03/2018
 
Description NEUROPRION Use of RNAi for treatment of inherited prion disease (14.4m euros across 41 participants)
Amount £90,000 (GBP)
Organisation European Commission (EC) 
Sector Public
Country European Union (EU)
Start 09/2007 
End 08/2009
 
Description consolidator award
Amount £1,800,000 (GBP)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 04/2016 
End 03/2021
 
Description experimental medicine grant
Amount £50,000 (GBP)
Organisation MRC Dementias Platform UK (DPUK) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 07/2017 
End 06/2019
 
Title NFH-Cre/MloxP mice 
Description cre deleter mice in neurons floxed prp mice crossed led to adult onset knockout of prp in neurons 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2006 
Provided To Others? Yes  
Impact reversal prion disease widely used mouse model 
 
Description ISRIB-like substances 
Organisation AstraZeneca
Department MedImmune
Country United States of America 
Sector Private 
PI Contribution we will test neuroprotective effects of new compounds in mice
Collaborator Contribution generation of compounds in vitro testing
Impact none yet
Start Year 2016
 
Description ISRIB-like substances 
Organisation University of Cambridge
Department Department of Chemistry
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution we will test neuroprotective effects of new compounds in mice
Collaborator Contribution generation of compounds in vitro testing
Impact none yet
Start Year 2016
 
Description In-vivo PET imagining of Neurodegeneration 
Organisation University of Cambridge
Department Wolfson Brain Imaging Centre
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution mice for the study and biochemical and histological analyses for confirmation of disease progression and efficacy of treatment.
Collaborator Contribution development and preparations of PET radiotracers for imaging research PET data acquisition and analysis
Impact none yet
Start Year 2013
 
Description Single molecule imaging of synaptic protein dynamics in neurodegeneration 
Organisation University of Kyoto
Department Institute of Integrated Cell Material Sciences
Country Japan 
Sector Academic/University 
PI Contribution Structural synaptic plasticity analysis in primary neuronal cultures of wild type and neurodegenerative disease mouse models
Collaborator Contribution Single-molecule imaging and super-resolution imaging o synaptic plasticity in primary neuronal cultures of wild type and neurodegenerative disease mouse models
Impact none yet
Start Year 2014
 
Description pharmacokinetic studies on PERK inhibitors 
Organisation GlaxoSmithKline (GSK)
Department GSK Oncology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution mechanism of neurodegeneration in prion disease and use of compounds to modulate disease progression
Collaborator Contribution PK and PD analyses GSK supplied compounds LC/MS-MS Compound production
Impact Oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice. Moreno JA, Halliday M, Molloy C, Axten JM, Willis AE, Ortori CA, Barrett DA, Fischer PM and Mallucci GR. Science Translational Medicine, 2013, 5,206ra138. Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Guerra Martin M, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, M Bushell and Mallucci GR*. Nature 2012, 485, 507-11
Start Year 2012
 
Description pharmacokinetic studies on PERK inhibitors 
Organisation Medicinal Chemistry; University of Nottingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution mechanism of neurodegeneration in prion disease and use of compounds to modulate disease progression
Collaborator Contribution PK and PD analyses GSK supplied compounds LC/MS-MS Compound production
Impact Oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice. Moreno JA, Halliday M, Molloy C, Axten JM, Willis AE, Ortori CA, Barrett DA, Fischer PM and Mallucci GR. Science Translational Medicine, 2013, 5,206ra138. Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Guerra Martin M, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, M Bushell and Mallucci GR*. Nature 2012, 485, 507-11
Start Year 2012
 
Description pharmacokinetic studies on PERK inhibitors 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution mechanism of neurodegeneration in prion disease and use of compounds to modulate disease progression
Collaborator Contribution PK and PD analyses GSK supplied compounds LC/MS-MS Compound production
Impact Oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice. Moreno JA, Halliday M, Molloy C, Axten JM, Willis AE, Ortori CA, Barrett DA, Fischer PM and Mallucci GR. Science Translational Medicine, 2013, 5,206ra138. Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Guerra Martin M, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, M Bushell and Mallucci GR*. Nature 2012, 485, 507-11
Start Year 2012
 
Description pharmacokinetic studies on PERK inhibitors 
Organisation University of Nottingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution mechanism of neurodegeneration in prion disease and use of compounds to modulate disease progression
Collaborator Contribution PK and PD analyses GSK supplied compounds LC/MS-MS Compound production
Impact Oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice. Moreno JA, Halliday M, Molloy C, Axten JM, Willis AE, Ortori CA, Barrett DA, Fischer PM and Mallucci GR. Science Translational Medicine, 2013, 5,206ra138. Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Guerra Martin M, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, M Bushell and Mallucci GR*. Nature 2012, 485, 507-11
Start Year 2012
 
Description 28th Cambridge Festival of Neuroscience Keynote lecture "The treatment of dementia: new directions", Cambridge, UK, March 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public lecture: 28th Cambridge Festival of Neuroscience: "The treatment of dementia: new directions", Cambridge, UK, March 2016
Year(s) Of Engagement Activity 2016
 
Description Anne Silk Lecturer, Royal Society of Medicine, London, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact public lecture on progress in treatment of neurodegeneration
Year(s) Of Engagement Activity 2014
URL https://www.rsm.ac.uk/events/events-listing/2013-2014/groups/public-engagement-programme/pee07-anne-...
 
Description BBC radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact naked scientist radio interview about hibernation and Alzheimer's
Year(s) Of Engagement Activity 2016
URL http://www.thenakedscientists.com/HTML/podcasts/naked-scientists/show/20160119/
 
Description East midlands medical student conference: Keynote 'INSPIRE' lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact unknown
Year(s) Of Engagement Activity 2014
 
Description Frank May Medal for Excellence in Research and Outstanding Future Promise; University of Leicester, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact public lecture discussing medical advances
Year(s) Of Engagement Activity 2012
 
Description MRC PEN event 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact public panel debate between writers and scientists " barriers to creativity"
Royal geographical society
public debate and questions

MRC website
PEN website
Year(s) Of Engagement Activity 2009
 
Description Media interviews for STM paper 2013 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact MRC scientists halt neurodegeneration in mice (BBC 4 Today programme, 07.12) also interviews on BBC, ITV, Channel 5, Sky, CNN, ABC, Al jazeera, local radio-stations
The Independent (front page) with additional online commentary
The Daily Express (front page)
Daily Mirror (front page)
The Sun (page 4) Online version unavailable
Daily Mail (page 5)
The Guardian (page 6)
The Daily Record (page 5)
The Scotsman p13
The Herald p5 Online version unavailable
BBC online
ITV
Sky News
Channel 4
The Daily Telegraph (page 14)

The story was also reported without an MRC mention in The Times (front page, online version unavailable)

Plus...innumerable regional newspapers, radio and TV outlets - particularly in the Leicester area!! - and international outlets from CNN to ABC to The Times of India, Time magazine, Spanish, Italian, Brazilian, Polish, Turkish, French and German outlets.
A pill for neurodegenerative disease? Not yet, but we're getting closer (BBC News Online)
The Guardian
SKY News
BBC World Service
ITV
BBC World Business Report
Radio 5
BBC Breakfast

The Daily Mirror (page 8) highlighted the research and asked what other diseases can we hope to defeat. Online version unavailable
The Sunday Times, News Review page 2, Vivienne Parry
(BBC News Online) The Guardian
SKY News
BBC World Service
ITV
BBC World Business Report
Radio 5

The Daily Mirror (page 8) highlighted the research and asked what other diseases can we hope to defeat. Online version unavailable
The Sunday Times, News Review page 2, Vivienne Parry

Huge interest into the Unit's research
Year(s) Of Engagement Activity 2013,2014
 
Description Nature podcast 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact nature podcast about discovery of hibernation and synaptic regeneration and role in neuroprotection
Year(s) Of Engagement Activity 2015
URL http://www.nature.com/nature/podcast/index-2015-01-15.html
 
Description Plenary speaker and panelist at International Monetary Fund First TalentNomics Conference: Innovation, Economic Growth, and the Empowerment of Women, Washington DC, USA, November 2015. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Plenary speaker and panelist at International Monetary Fund First TalentNomics Conference: Innovation, Economic Growth, and the Empowerment of Women, Washington DC, USA, November 2015.
Year(s) Of Engagement Activity 2015
 
Description Science Festival in Genova 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact public interest high

public interest
Year(s) Of Engagement Activity 2012
 
Description Television interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact discussed our research which was hailed as "turning point in search for medicines to control and prevent Alzheimer's"
Year(s) Of Engagement Activity 2013
URL http://www.bbc.co.uk/news/health-24462699.
 
Description UK Conference of Science Journalists 2012 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact dialogue with science writers

interest in science reporting
Year(s) Of Engagement Activity 2012
 
Description Unit Open Day 2013 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Over 500 members of the public visited the Unit

Members of the public were very appreciative.
Students asked to come and carry out work experience in the Unit.
Year(s) Of Engagement Activity 2013
URL http://tox.mrc.ac.uk/
 
Description biology in action 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Biology in Action is a very popular annual day, which sets out to give students a stimulating day of biology in five wide-ranging sessions, and helps them and their teachers keep up to date with developments and issues. We aim to provide students with inspiration to pursue their studies at a higher level through talks that go beyond the curriculum.
Year(s) Of Engagement Activity 2016
 
Description media interviews 2007 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact numerous interviews to BBC radio, US radio
science press
national press

widespread reporting in science and mass media
radio 4 interview 'science now'
Year(s) Of Engagement Activity 2007
 
Description mrc annual report 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact interviewed as one of MRC's 'people behind discovery'

positive feedback, applicants to work with me
Year(s) Of Engagement Activity 2007
 
Description nottingham inspire 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact 400 medical students
careers in science and medicine
Year(s) Of Engagement Activity 2014
 
Description nottingham inspire 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact 400 medical students
careers in science and medicine
Year(s) Of Engagement Activity 2014
 
Description press interviews 2008 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact press interviews broadsheets science journals BBC Radio 4 science now

widespread dissemination of research
Year(s) Of Engagement Activity 2008
 
Description radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact http://www.thenakedscientists.com/HTML/podcasts/naked-scientists/show/20160119/
Year(s) Of Engagement Activity 2016
URL http://www.thenakedscientists.com/HTML/podcasts/naked-scientists/show/20160119/
 
Description schools careers in science talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact pupils interested in science
work experience in my lab

work experience and science interests
Year(s) Of Engagement Activity 2010,2011,2012
 
Description toxicology open day 2010 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact presentation to graduate students

top performer voted by students!
Year(s) Of Engagement Activity 2010
 
Description work experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact work student for 1 week in my lab
work experience undergraduate for 10wks

positive experience further applicants
Year(s) Of Engagement Activity 2010,2012,2013,2014
 
Description work highlighted British Neuroscience Bulletin 2012 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact highlight of groups reseracj

generated much interest adn phd applications
Year(s) Of Engagement Activity 2012