Altered RNA metabolism in neurodegeneration

Lead Research Organisation: King's College London

Abstract

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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.

A wide variety of neurodegenerative diseases are caused by mutations in RNA binding proteins. However, the pathogenic mechanisms leading to these disorders are not yet well understood. We study the FUS gene (Fused in Sarcoma), which encodes a conserved RNA-binding protein. Mutations in this gene can lead to the development of Amyotrophic Lateral Sclerosis (ALS), the most common motor neuron (MN) disease in human adults. While FUS is a nucleocytoplasmic shuttling protein, it is mainly nuclear at steady state. Most ALS-associated FUS mutations disrupt the nuclear localization signal (NLS), leading to nuclear exclusion and cytoplasmic FUS aggregates in neurons and glial cells of these ALS patients. FUS is also a major protein component in pathologic cytoplasmic inclusions in some cases of Frontotemporal Lobar Degeneration (FTLD-FUS). However, unlike for FUS-linked ALS, the molecular cause for cytoplasmic mislocalisation in FUS-linked FTLD is unknown and no vertebrate model for FTLD-FUS is available. Therefore, the potential pathomechanisms in FUS-linked FTLD will have to be inferred from the insights from FUS-linked ALS models and its physiological functions.
FUS functions in several processes required for proper gene expression, such as transcription, pre-mRNA splicing, and miRNA processing. However, its precise role in these processes and most of its targeted RNAs are, as of yet, unknown. The combination of this lack of knowledge with the lack of FTLD-FUS models has led me and my research group to the conviction that understanding the biological function(s) of normal FUS will be one of the keys to gain insight into the role of FUS-associated neurodegeneration. Furthermore, this will allow us to fully interpret our results from our parallel investigation on the pathomechanisms of FUS-linked ALS using in vitro and in vivo models of disease. The results of our research are expected to reveal the molecular mechanisms implicated FUS-associated ALS and FTLD and identify targets for the development of therapeutic approaches.

Publications

10 25 50
 
Title UK DRI Opening event artwork 
Description The artist painted our stem cell derived motor neurons which were exposed at the UK DRI opening event. 
Type Of Art Artwork 
Year Produced 2019 
Impact Making science visible for the public and visualizing our generated output. 
 
Description Academic Mentor for PhD students within the Department
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Mentoring PhD Students Holding Scientifc Integrity Workshop Organizing Scientific Integrity Lectures 1:1 Meetings with Students
 
Description Dissecting the pathobiology of MND using FUS Delta14 mouse model
Amount £100,000 (GBP)
Funding ID 867-791 Note: PI: Anny Devoy; Co-I: Marc-David Ruepp (KCL-UK DRI), Helene Plun-Favreu (UCL) 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 06/2020
 
Description Identification of converging minor intron splicing defects in ALS and elucidation of their therapeutic ptoential
Amount £233,386 (GBP)
Funding ID Ruepp/Apr19/872-791 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2020 
End 12/2022
 
Title CRISPR-trap 
Description CRISPR-trap allows the efficient generation of clean knockouts in cells by combining CRISPR/Cas9 with gene traps. 
Type Of Material Cell line 
Year Produced 2018 
Provided To Others? Yes  
Impact Better model generation Requestes of generated cell lines and plasmids by laboratories in the UK, Canada, Germany 
URL https://bio-protocol.org/e3052
 
Description Collaboration with Adrian Isaacs and Sarah Mizielinska on C9orf72 ALS 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation of an in vitro stem cell model of C9orf72 ALS
Collaborator Contribution Help in exchange matrix design for genome editing and exchange of material This is a DRI cross-centre collaboration
Impact The collaboration just started, no outputs yet
Start Year 2019
 
Description Collaboration with Adrian Isaacs and Sarah Mizielinska on C9orf72 ALS 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation of an in vitro stem cell model of C9orf72 ALS
Collaborator Contribution Help in exchange matrix design for genome editing and exchange of material This is a DRI cross-centre collaboration
Impact The collaboration just started, no outputs yet
Start Year 2019
 
Description Collaboration with Mihaela Zavolan (Uni Bas) and Eva Hedlund (Karolinska) on the physiological functions of FUS and ALS-FUS pathomechansims 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Generation of isogenic MNs via genome editing Transcriptomic profiling of in vitro ALS-MNs and mechanistic research on the physiological function of FUS
Collaborator Contribution Michael Zavolan: Computational analysis of data Eva Hedlund: Single Cell Sequencing of iPSC-derived MNs The collaborators are outside of the UK DRI
Impact Manuscript in preparation
Start Year 2017
 
Description Collaboration with Mihaela Zavolan (Uni Bas) and Eva Hedlund (Karolinska) on the physiological functions of FUS and ALS-FUS pathomechansims 
Organisation University of Basel
Department Biozentrum Basel
Country Switzerland 
Sector Academic/University 
PI Contribution Generation of isogenic MNs via genome editing Transcriptomic profiling of in vitro ALS-MNs and mechanistic research on the physiological function of FUS
Collaborator Contribution Michael Zavolan: Computational analysis of data Eva Hedlund: Single Cell Sequencing of iPSC-derived MNs The collaborators are outside of the UK DRI
Impact Manuscript in preparation
Start Year 2017
 
Description Collaboration with Pietro Fratta on the auto regulation of FUS 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Studying the auto regulation of FUS in cancer cell lines
Collaborator Contribution Studying the auto regulation of FUS in an in vivo oder of FUS ALS The Collaboration is outside the UK DRI
Impact Joint pre-print bioRxiv 567735; doi: https://doi.org/10.1101/567735
Start Year 2018
 
Description Collaboration with Prof Chris Shaw 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution In vitro models of ALS FUS and provision of material and molecular biology experience
Collaborator Contribution Generation of novel iPSC models, exchange of material and data UK DRI internal collaboration
Impact No outputs yet
Start Year 2018
 
Description Collaboration with Prof Frédéric Allain on the physiological functions of Fused in Sarcoma 
Organisation ETH Zurich
Country Switzerland 
Sector Academic/University 
PI Contribution Currently working together on two further manuscripts of the Function of FUS. We provide in vivo and molecular biology data, while the Allain group focuses on structural characterization of FUS.
Collaborator Contribution Structural characterization of FUS bound to RNA The collaborator is outside of the UK DRI
Impact Joint publications. The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity. Loughlin FE, Lukavsky PJ, Kazeeva T, Reber S, Hock EM, Colombo M, Von Schroetter C, Pauli P, Cléry A, Mühlemann O, Polymenidou M, Ruepp MD, Allain FH. Mol Cell. 2019 Feb 7;73(3):490-504.e6. doi: 10.1016/j.molcel.2018.11.012. Epub 2018 Dec 20. Three further manuscripts in preparation.
Start Year 2013
 
Description Collaboration with Prof Silvia Barabino and Prof Oliver Mühlemann on FUS' function in DNA damage and the impact of phase separation on this process 
Organisation University of Bern
Country Switzerland 
Sector Academic/University 
PI Contribution Studying the physiological functions of FUS and defective mechanisms in ALS, Characterizing the interactomes of non-LLPS and LLPS FUS
Collaborator Contribution Studying the physiological functions of FUS and defective mechanisms in ALS related to DNA Damage The collaborator is outside of the UK DRI
Impact Two pre-prints that currently submitted/in peer-review bioRxiv 806158; doi: https://doi.org/10.1101/806158 bioRxiv 798884; doi: https://doi.org/10.1101/798884
Start Year 2013
 
Description Collaboration with Prof Silvia Barabino and Prof Oliver Mühlemann on FUS' function in DNA damage and the impact of phase separation on this process 
Organisation University of Milano-Bicocca
Country Italy 
Sector Academic/University 
PI Contribution Studying the physiological functions of FUS and defective mechanisms in ALS, Characterizing the interactomes of non-LLPS and LLPS FUS
Collaborator Contribution Studying the physiological functions of FUS and defective mechanisms in ALS related to DNA Damage The collaborator is outside of the UK DRI
Impact Two pre-prints that currently submitted/in peer-review bioRxiv 806158; doi: https://doi.org/10.1101/806158 bioRxiv 798884; doi: https://doi.org/10.1101/798884
Start Year 2013
 
Description Collaboration with Prof. Oliver Mühlemann, University of Bern 
Organisation University of Bern
Country Switzerland 
Sector Academic/University 
PI Contribution Generation of a Progranulin iPSC model. We aided in the design of the genome editing strategy
Collaborator Contribution A PhD student of the Mühlemann Lab visited the lab and performed genome editing and learned neuronal differentiations.
Impact The collaboration is ongoing, no outcomes yet.
Start Year 2019
 
Description Invited Speaker at MRC Harrell 25.06.2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Presentation of our work on FUS-ALS and the impact of altered RNA metabolism in Neurodegeneration. The presentation has resulted in knowledge exchange and informal collaborations
Year(s) Of Engagement Activity 2019
 
Description Invited Speaker at the Centre for Genetic Engineering and Biotechnology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Presentation and discussion of our recent data on altered RNA metabolism in ALS-FUS
Year(s) Of Engagement Activity 2019
 
Description Invited speaker at the UK-Isreal UK Dementia Prevention Conference in Tel-Aviv 17-19.06 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of our work on altered RNA metabolism in Neurodegeneration
Year(s) Of Engagement Activity 2019
 
Description Session Chair at the Austrian/Swiss RNA Meeting Fuschelsee 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I chaired one session of this meeting that combined RNA research groups from Austria and researchers from Switzerland being members of the National Centre of Competence in Research NCCR RNA and Disease
Year(s) Of Engagement Activity 2019
 
Description UK DRI at King's Opening Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact This symposium marked the official opening of the UK Dementia Research Institute King's College London centre. From 18-19 February 2019, researchers showcased new insights into neurodegenerative disease mechanisms including international expert keynote lectures. 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