Single molecule nucleocytoplasmic transport dynamics in FTD/ALS

Lead Research Organisation: King's College London

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

This programme will explore how nucleocytoplasmic transport is affected in FTD and ALS at the single molecule level, and how this links to common disease pathologies. Studies will focus on disease-associated proteins containing LCDs, such as those identified pathologically in individuals carrying C9orf72 mutations. This multidisciplinary work will utilise super resolution microscopy to investigate the dynamics of single molecule
cargo through the nuclear pore combined with biophysical studies to study phase transitioning of nuclear pore selection barriers to unveil unique disease pathomechanisms often overlooked from bulk endpoint analyses. Methodologies developed in these studies will be broadly applied across different disease models, from transduced cell lines to patient-derived induced pluripotent stem cells (and adapted for use in Drosophila and
mouse models), utilising transcriptomics and proteomics. Key mechanistic findings will be validated in FTD and ALS patient tissues to ensure disease relevance.

Publications

10 25 50
 
Title Artwork commemorating the opening event of the DRI@KCL 
Description Spray painted artwork inspired by the research undertaken by the DRI@KCL teams - some of which was provided by researchers in my team. 
Type Of Art Artwork 
Year Produced 2019 
Impact Increased impact of the importance of dementia research and the people it affects. 
URL https://twitter.com/SMizielinska/status/1097561702810439680
 
Description Departmental PhD academic mentor
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Research and pastoral support to PhD students within the Department of Basic and Clinical Neuroscience, KCL, to enhance their academic performance Includes one-to-one meetings and organisation of annual student-led symposium Meetings - encouragement and engagement of students to their academic studies and beyond. Showing them that the department does care about their well being and progress. Symposium - Education and awareness to local PhD students of breadth of research in the department including fundamental and clinical research. Students very engaged and more open to question as designed to have no PIs present. More interaction between PhD students.
URL https://www.eventbrite.co.uk/e/kcl-ioppn-basic-clinical-neuroscience-phd-symposium-tickets-505972276...
 
Description Supporting local Women in Science movement (talks, discussion panels etc)
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact - pay negotiation workshop: Changing attitudes and approaches to pay negotiation to overcome gender pay gap. Open to all, women/men, all levels. - discussion session for any gender equality issues and increase visibility of female role models
URL https://www.eventbrite.co.uk/o/women-of-the-wohl-17532893112
 
Description ARUK Major Project Grant (charity)
Amount £196,585 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2021 
End 06/2023
 
Description BBSRC LIDO iCASE Studentship (Government/industry)
Amount £118,294 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2021 
End 01/2025
 
Description Identifying novel modifiers of nucleocytoplasmic transport in C9orf72-FTD using haploid genetics (charity)
Amount £50,000 (GBP)
Funding ID ARUK-PPG2018B-024 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 09/2020
 
Description MNDA Biomedical Research Project Grant (charity)
Amount £223,386 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2020 
End 12/2022
 
Description MNDA PhD Studentship (charity)
Amount £97,311 (GBP)
Funding ID Mizielinska/Oct19/896-792 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2021 
End 01/2024
 
Description MRC Doctoral Partnership in Biomedical Sciences (government)
Amount £93,000 (GBP)
Organisation MRC Doctoral Training Program 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 03/2022
 
Description Van Geest Funds (philanthropic)
Amount £100,000 (GBP)
Organisation University of Leicester 
Department John and Lucille van Geest Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 02/2018 
End 09/2021
 
Title Identifying novel modifiers of nucleocytoplasmic transport in C9orf72-FTD using haploid genetics 
Description We have used haploid knockout cells to provide a clean knockout background for the effect of deletion of genes on nucleocytoplasmic transport of a shuttling report and TDP-43 
Type Of Material Technology assay or reagent 
Year Produced 2021 
Provided To Others? No  
Impact This will be a useful method to identify or assess the effect of knockout of genes on nucleocytoplasmic transport of any protein 
 
Title Single molecule nucleocytoplasmic transport in live cells 
Description Novel method for the monitoring of single molecule nucleocytoplasmic transport in intact live cells 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2020 
Provided To Others? No  
Impact Using to inform on C9orf72 pathomechanisms 
 
Description Biophysical characterisation of nuclear pore proteins and alterations in disease 
Organisation Flanders Institute for Biotechnology
Country Belgium 
Sector Charity/Non Profit 
PI Contribution Leading project to characterise nuclear pore proteins and alterations in disease
Collaborator Contribution DRI collaboration - Annalisa Pastore - providing biophysical expertise for characterisation External - Broder Schmidt - providing expertise into in vitro nuclear pore hydrogel droplets Ludo Van Den Bosch - hosting Mizielinska postdoc for DLS analysis
Impact No outputs
Start Year 2018
 
Description Biophysical characterisation of nuclear pore proteins and alterations in disease 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Leading project to characterise nuclear pore proteins and alterations in disease
Collaborator Contribution DRI collaboration - Annalisa Pastore - providing biophysical expertise for characterisation External - Broder Schmidt - providing expertise into in vitro nuclear pore hydrogel droplets Ludo Van Den Bosch - hosting Mizielinska postdoc for DLS analysis
Impact No outputs
Start Year 2018
 
Description Biophysical characterisation of nuclear pore proteins and alterations in disease 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Leading project to characterise nuclear pore proteins and alterations in disease
Collaborator Contribution DRI collaboration - Annalisa Pastore - providing biophysical expertise for characterisation External - Broder Schmidt - providing expertise into in vitro nuclear pore hydrogel droplets Ludo Van Den Bosch - hosting Mizielinska postdoc for DLS analysis
Impact No outputs
Start Year 2018
 
Description C9orf72 mutation and TDP-43 modifier studies using haploid knockout cell lines 
Organisation Institute of Molecular Biotechnology, Vienna, Austria
Country Austria 
Sector Academic/University 
PI Contribution Co-design and supervision of project with Jean-Marc Gallo, imaging expertise
Collaborator Contribution Jean-Marc Gallo - co-design and co-supervision of project Josef Penninger - expertise and provision of Haplobank lines
Impact No outputs yet Successful ARUK Pilot grant
Start Year 2017
 
Description C9orf72 mutation and TDP-43 modifier studies using haploid knockout cell lines 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-design and supervision of project with Jean-Marc Gallo, imaging expertise
Collaborator Contribution Jean-Marc Gallo - co-design and co-supervision of project Josef Penninger - expertise and provision of Haplobank lines
Impact No outputs yet Successful ARUK Pilot grant
Start Year 2017
 
Description C9orf72 mutation and TDP-43 modifier studies using haploid knockout cell lines 
Organisation University of British Columbia
Department UBC/BC Cancer Agency
Country Canada 
Sector Academic/University 
PI Contribution Co-design and supervision of project with Jean-Marc Gallo, imaging expertise
Collaborator Contribution Jean-Marc Gallo - co-design and co-supervision of project Josef Penninger - expertise and provision of Haplobank lines
Impact No outputs yet Successful ARUK Pilot grant
Start Year 2017
 
Description Characterisation of C9orf72 ips 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Characterisation of laminopathy in C9orf72 iPS
Collaborator Contribution DRI collaboration - Chris Shaw - Provision of patient C9orf72 iPS lines KCL - Manolis Fanto - laminopathy expertise
Impact Produced preliminary data for a successful grant application
Start Year 2019
 
Description Creation of an endogeously tagged TDP-43 iPSC model 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We conceived the idea and are testing appropriate tags
Collaborator Contribution Gene editing with CRISPR/Cas9
Impact None so far
Start Year 2021
 
Description Detection of C9orf72 DPRs by mass spectrometry 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution C9orf72 expertise and generation of samples for testing
Collaborator Contribution Jemeen Sreedharan, KCL - optimisation of immunoprecipitation for sample enrichment Peter O'Connor, Oxford - mass spectrometry
Impact None so far
Start Year 2020
 
Description Detection of C9orf72 DPRs by mass spectrometry 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution C9orf72 expertise and generation of samples for testing
Collaborator Contribution Jemeen Sreedharan, KCL - optimisation of immunoprecipitation for sample enrichment Peter O'Connor, Oxford - mass spectrometry
Impact None so far
Start Year 2020
 
Description Generation of isogenic C9orf72 knock-in iPS lines and investigation of converging pathomechanisms in ALS 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Mizielinska and Ruepp co-designed this project.
Collaborator Contribution DRI collaboration - Adrian Isaacs and external - Tom Cunningham (Harwell) collaboration is providing us with C9orf72 repeat donor Shared technician and postdoc with Marc-David Ruepp
Impact Mizielinska and Ruepp successful grant application Collaboration is multidisciplinary from ips to ms modelling
Start Year 2019
 
Description Generation of isogenic C9orf72 knock-in iPS lines and investigation of converging pathomechanisms in ALS 
Organisation MRC Harwell
Country United Kingdom 
Sector Academic/University 
PI Contribution Mizielinska and Ruepp co-designed this project.
Collaborator Contribution DRI collaboration - Adrian Isaacs and external - Tom Cunningham (Harwell) collaboration is providing us with C9orf72 repeat donor Shared technician and postdoc with Marc-David Ruepp
Impact Mizielinska and Ruepp successful grant application Collaboration is multidisciplinary from ips to ms modelling
Start Year 2019
 
Description Generation of isogenic C9orf72 knock-in iPS lines and investigation of converging pathomechanisms in ALS 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Mizielinska and Ruepp co-designed this project.
Collaborator Contribution DRI collaboration - Adrian Isaacs and external - Tom Cunningham (Harwell) collaboration is providing us with C9orf72 repeat donor Shared technician and postdoc with Marc-David Ruepp
Impact Mizielinska and Ruepp successful grant application Collaboration is multidisciplinary from ips to ms modelling
Start Year 2019
 
Description Interaction between nucleocytoplasmic transport dysfunction and autophagy in C9orf72-FTD/ALS 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Knowledge and expertise in nucleocytoplasmic transport
Collaborator Contribution Patricia Gomez-Suaga - Knowledge and expertise in autophagy
Impact Successful MNDA PhD Studentship
Start Year 2019
 
Description Laminopathy in C9orf72-FTD/ALS 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution C9orf72 expertise, cellular studies, microscopy (confocal and super-resolution)
Collaborator Contribution Manolis Fanto - discovered new cell death mechanism (karyoptosis), drosophila studies Graham Frazer, AstraZeneca - design of small molecules
Impact Joint MRC-DTP Studentship with Fanto 2018 Successful ARUK Project Grant, awarded 2020 Successful BBSRC LIDO PhD Studentship with AstraZeneca to commence 2021 Multidisciplinary: chemistry, cellular, drosophila
Start Year 2018
 
Description Laminopathy in C9orf72-FTD/ALS 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution C9orf72 expertise, cellular studies, microscopy (confocal and super-resolution)
Collaborator Contribution Manolis Fanto - discovered new cell death mechanism (karyoptosis), drosophila studies Graham Frazer, AstraZeneca - design of small molecules
Impact Joint MRC-DTP Studentship with Fanto 2018 Successful ARUK Project Grant, awarded 2020 Successful BBSRC LIDO PhD Studentship with AstraZeneca to commence 2021 Multidisciplinary: chemistry, cellular, drosophila
Start Year 2018
 
Description Super-resolution imaging with novel quantum dot-antibody conjugation or aptamer-PAINT 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Super-resolution imaging expertise, testing of quantum dot-antibody conjugates or aptamers
Collaborator Contribution DRI collaboration - Cho/Klenerman design of quantum-dot antibody conjugates, Pastore - design and biophysical testing of aptamers
Impact None so far Multidisciplinary - chemistry, electrophysiology, microscopy
Start Year 2020
 
Description Super-resolution imaging with novel quantum dot-antibody conjugation or aptamer-PAINT 
Organisation University of Cambridge
Department Cambridge Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Super-resolution imaging expertise, testing of quantum dot-antibody conjugates or aptamers
Collaborator Contribution DRI collaboration - Cho/Klenerman design of quantum-dot antibody conjugates, Pastore - design and biophysical testing of aptamers
Impact None so far Multidisciplinary - chemistry, electrophysiology, microscopy
Start Year 2020
 
Description 1st European C9orf72 Workshop - Munich 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I presented and chaired a session at an informal workshop/meeting on C9orf72 to bring the European community closer together. All attendees presented including unpublished work. After the meeting we all shared a slide of haves/wants for research collaborations.
Year(s) Of Engagement Activity 2018
 
Description In2Science scheme, hosting school students from disadvantaged background 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Hosted school students from disadvantaged background through In2Science scheme (summer 2019)
Experience for school students in research
Helped with university application
teachers and students thankful and increased motivation for applying for science subject at university
Year(s) Of Engagement Activity 2019
 
Description Interview with Alzheimer's Society 
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 Public/other audiences
Results and Impact Interview with Alzheimer's Society to generate media video for promotion of research into dementia. 1776 views on youtube, 7900 views on facebook.
Shared within university as a great example of early career researchers making an impact in research.
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=qc9e1KaPF20&list=PL6Qsh0P6vDZJ5rKxArhTqrUg_C4yJP3SE&index=9&t=0s
 
Description Invited speaker Alzheimer's Research UK Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited speaker Alzheimer's Research UK Annual Meeting
Formed new collaborations from this
Year(s) Of Engagement Activity 2018
 
Description Invited speaker FTD UK Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited speaker FTD UK Annual Meeting
Engaged with FTD community, feedback on my researhc
Year(s) Of Engagement Activity 2019
 
Description Invited speaker KCL Division of Neuroscience Annual Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited speaker KCL Division of Neuroscience Annual Meeting
Better awareness of local neuroscience community
Better awareness of community of my research and techniques, and of disease adn genetics
Year(s) Of Engagement Activity 2018
 
Description Invited speaker MRC Harwell 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Invited speaker MRC Harwell
New collaboration formed, shared scientific tools
Year(s) Of Engagement Activity 2019
 
Description Invited speaker Nuclear Transport 19 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker Nuclear Transport 19
New collaborations in nuclear transport field
Gained feedback for our research which added new experiments for research plan
New future collaborations
Year(s) Of Engagement Activity 2019
 
Description Japan-UK Neuroscience Symposium 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to speak at a joint meeting of around 50 people between the MRC (UK) and AMED (Japan) to promote international medical research collaboration, by combining world-class scientific expertise to help advance human health, including dementia as one of their initial priorities.Talks and posters encouraged much scientific discussion, and discussion of funding for joint PhD studentships between UK and Japan.
Year(s) Of Engagement Activity 2019
URL https://mrc.ukri.org/news/browse/new-uk-japan-medical-research-collaboration/
 
Description KCL Parade of Stars 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Parade of Stars is a showcase of exciting and innovative research, celebrating academic success across the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at KCL. It is also a celebration of the excellence, inclusivity and cooperation at IoPPN. Prompted discussion around multidisciplinary research with Dean and also with students.
Year(s) Of Engagement Activity 2018
URL https://www.kcl.ac.uk/ioppn/news/special-events/parade/parade-of-stars-2018
 
Description Represented KCL at the 1st UKDRI Annual Connectome (September 2018, Reading) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Represented KCL at the 1st UKDRI Annual Connectome (September 2018, Reading)
New collaborations
Year(s) Of Engagement Activity 2018
 
Description UK DRI at King's Opening Symposium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A lively symposium marked the official opening of the UK Dementia Research Institute King's College London centre. Over two days, 18-19 February 2019, researchers showcased new insight into neurodegenerative disease mechanisms to ultimately design smarter diagnostics and effective therapeutic, including international expert keynote lectures. We also held a celebration of the UK DRI at King's researchers' commitment to ending dementia including a talk on the importance of diversity in research along with an interactive session which gave attendees to opportunity literally "tear down dementia" to reveal some incredible art that captures the goals of the centre to find treatments for dementia. Many people commented and tweeted that this was a great event, stimulating many discussions about dementia research and engagement and interest from students/researchers/industry for new collaborations.
Year(s) Of Engagement Activity 2019
URL https://ukdri.ac.uk/news-and-events/kingslaunch