RNA processing proteins and neurodegeneration: exploring mechanisms and modelling disease
Lead Research Organisation:
King's College London
Department Name: UNLISTED
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
Recent genetic and pathological discoveries have placed the RNA-processing proteins, TDP-43 and FUS, centre stage in the pathogenesis of ALS and FTLD-U. Here we present evidence that FUS and TDP-43 mislocalise and aggregate in FTLD-U patients with PGRN mutations. Aberrant processing of transcripts may cause neurodegenration due to a loss of function; however, these proteins also aggregate in affected neurons and may cause a toxic gain in function. The main aim of this proposal is to generate cellular and animal models to determine which mechanism is predominant (or whether both are necessary) and identify the events that initiate neurodegeneration. We will: _ Generate and characterise cellular models of PGRN, TDP-43 and FUS mediated neurodegeneration. _ Generate and characterise zebrafish and mouse models of PGRN, TDP-43 and FUS mediated neurodegeneration. _ Identify the physiological DNA and RNA binding targets of TDP-43 and FUS in cells and animal tissues. _ Define the transcriptional and proteomic signatures for loss and/or gain of function for PGRN, TDP-43 and FUS in cellular and animal models. _ Interrogate FTLD and ALS nervous tissues for loss and/or gain of function transcriptomic or proteomic signatures and compare these to other neurodegenerative disorders _ Identify the major sites of in vivo phosphorylation of TDP-43 and FUS, the kinases responsible and the functional consequences of these post translational modifications.
Organisations
People |
ORCID iD |
Publications
Ahmeti KB
(2013)
Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1.
in Neurobiology of aging
Akimoto C
(2014)
A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories.
in Journal of medical genetics
Al Khleifat A
(2019)
Telomere length is greater in ALS than in controls: a whole genome sequencing study.
in Amyotrophic lateral sclerosis & frontotemporal degeneration
Al-Chalabi A
(2014)
Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study.
in The Lancet. Neurology
Al-Chalabi A
(2017)
Gene discovery in amyotrophic lateral sclerosis: implications for clinical management.
in Nature reviews. Neurology
Al-Sarraj S
(2011)
p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS.
in Acta neuropathologica
Alami NH
(2014)
Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations.
in Neuron
Arnold ES
(2013)
ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.
in Proceedings of the National Academy of Sciences of the United States of America
Bajc Cesnik A
(2019)
Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies.
in Journal of cell science
Barker HV
(2017)
RNA Misprocessing in C9orf72-Linked Neurodegeneration.
in Frontiers in cellular neuroscience
| Description | Submission to Parliamentary Science and Technology Committee |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Permitted the use of hybrid embryos in research in UK |
| Description | Identification of compounds that enhance TDP43 clearance in ALS and FTD |
| Amount | £462,000 (GBP) |
| Organisation | Eli Lilly & Company Ltd |
| Sector | Private |
| Country | United Kingdom |
| Start | 12/2015 |
| End | 05/2020 |
| Description | King's Biomedical Sciences Institute PhD Studentship |
| Amount | £100,000 (GBP) |
| Organisation | King's College London |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 03/2014 |
| End | 10/2017 |
| Description | MNDA studentship |
| Amount | £87,502 (GBP) |
| Organisation | Motor Neurone Disease Association (MND) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2010 |
| End | 09/2013 |
| Description | MRC Case Studentship |
| Amount | £100,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2014 |
| End | 10/2018 |
| Description | PhD Studentship |
| Amount | £100,000 (GBP) |
| Organisation | King's College London |
| Department | Psychiatry Research Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 11/2010 |
| End | 11/2013 |
| Description | Programme Grant |
| Amount | £650,000 (GBP) |
| Organisation | Edmond J Safra Foundation |
| Sector | Charity/Non Profit |
| Country | Liechtenstein |
| Start | 07/2014 |
| End | 06/2019 |
| Description | Programme Grant FP7 |
| Amount | £666,323 (GBP) |
| Organisation | Spanish National Research Council (CSIC) |
| Sector | Public |
| Country | Spain |
| Start | 12/2010 |
| End | 12/2013 |
| Description | Project Grant |
| Amount | $100,000 (USD) |
| Organisation | The ALS Association |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 02/2012 |
| End | 06/2014 |
| Description | Studentship |
| Amount | £250,000 (GBP) |
| Organisation | British Society for the History of Science (BSHS) |
| Department | Darwin Trust of Edinburgh |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2014 |
| End | 09/2017 |
| Description | Testing chaperone gene therapy in a mouse model of Motor Neuron Disease and Fronto-Temporal Dementia |
| Amount | £120,000 (GBP) |
| Organisation | Peter Samuel Trustees |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2017 |
| End | 09/2021 |
| Description | Viral vector gene therapy for FTD and ALS: from constructs to clinical trials |
| Amount | £2,012,076 (GBP) |
| Organisation | UK Dementia Research Institute |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2019 |
| End | 08/2022 |
| Title | Clinical Trial of antisense oligonucleotide drug targeting the C9orf72 mRNA given intrathecally |
| Description | Clinical Trial of antisense oligonucleotide drug targeting the C9orf72 mRNA given intrathecally |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Early clinical assessment |
| Year Development Stage Completed | 2019 |
| Development Status | Under active development/distribution |
| Clinical Trial? | Yes |
| Impact | First in man trial of a drug targeting this genetic population |
| URL | https://clinicaltrials.gov/ct2/show/NCT03626012 |
| Company Name | NEUROGENEUS LTD |
| Description | Designi and manufacture of gene therapies for neurodegenerative disorders |
| Year Established | 2019 |
| Impact | None yet as just formed |
| Company Name | NEUROGENEUS LTD |
| Description | Developing adeno-associated viral vector gene therapies for neurodegenerative disorders |
| Year Established | 2021 |
| Impact | Raised `$100m Seed and Series A funding |
| Website | https://aviadobio.com/ |
| Description | Academic Lecture |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Sharing insights about gene testing in motor neuron disease and frontotemporal dementia |
| Year(s) Of Engagement Activity | 2022 |
| Description | Alinda Fernandes gave Lewisham Health Lectures at Lewisham Library - Talk Title: Alzheimer's Disease and Dementia |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | The talk was received very good feedback and triggered a series of stimulating conversations |
| Year(s) Of Engagement Activity | 2017 |
| Description | Alinda Fernandes poster presentation at MNDA Symposium Boston (2017) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | The poster was presented to mainly scientists during the poster session which enabled new collaborations. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Eva So Poster presentation at the Edmond J. Safra Memorial Lecture and Reception |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | Poster presentation to the audience and interactive communication and discussion about research work. Event included presentation and talks highlighting the modern day approach to research in Parkinson's and other neurodegenerative diseases and the frontline advances being made by different researchers, followed by question and answer session with the audience and direct communication at the poster reception. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Graham Cocks Poster submission - Poster presentation on CRISPR work for the 4th Genome editing conference, Oxford (GEOX 2018) |
| 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 a poster to international scientists. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Graham Cocks' participation |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Supporters |
| Results and Impact | This involved guiding a group of MNDA donors through a tour of research undertaken here at the Wohl. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Jenny Greig Legacy fundraising event |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Supporters |
| Results and Impact | People interested in supporting the MNDA came for a day of presentations to see the facility and the work that takes place here. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Jenny Greig poster presentation |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | Poster presentation at Stem Cell conference at Edinburgh University |
| Year(s) Of Engagement Activity | 2017 |
| Description | Jenny Greig poster presentation at MNDA conference in Boston |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Poster presentation at MNDA conference in Boston |
| Year(s) Of Engagement Activity | 2017 |
| Description | Lecture for Brain Conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Gene Therapy for ALS an FTD; Are we there yet? |
| Year(s) Of Engagement Activity | 2022 |
| Description | MND Genetics and Therapies |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Presentation on MND genetics and therapies to Palliative Health Care Professionals and members iof the public at a public centre |
| Year(s) Of Engagement Activity | 2018 |
| Description | MRC Centre Open Day |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Our Open Day is for patients and carers with approximately 150 attendees. We organise 8 laboratory demonstrations presented by PhD students and postdoctoral researchers around which small groups (6-8 persons) circulate. We also have a group of about 12 sixth form students who perform a laboratory experiment. At the end of the day the sixth formers present their results to the who audience and this is followed by an "Any Questions" session with clinical and non-clinical experts answering questions from the visitors. The Open Day has now been run on three occasions and each time has received universal acclaim from visitors. The report is also made available on our web site. |
| Year(s) Of Engagement Activity | 2008 |
| Description | Many media interviews TV, Radio, Newspapers, Radio |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Primary Audience | Public/other audiences |
| Results and Impact | Many media interviews TV, Radio, Newspapers, Radio Legislation modified |
| Year(s) Of Engagement Activity | 2008 |
| Description | Multi-site Phosphorylation Assays for Tau Protein and their relevance to Alzheimer's disease and other neurological disorders |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Poster presentation at American Society of Mass Spectrometry conference None |
| Year(s) Of Engagement Activity | 2008 |
| Description | Patient and Carers meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Each meeting has 40-60 attendees and lasts 1.5 hours with talk and questions Patients have come to our laboratory open day and are actively fundraising to create a studentship |
| Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010 |
| Description | Patient and Carers meeting |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | 40-60 Patients and Carers lasting 1.5 hours of talk and discussion Members of the audience are fundraising for a studentship for my laboratory |
| Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010 |
| Description | Presented to Members of Parliament |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Presented to parliamentary parties Legeislation changed |
| Year(s) Of Engagement Activity | 2008 |
| Description | Public Lecture to Aotea Centre, Auckland New Zealand |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Lecture on motor neuron disease therapies to lay audience |
| Year(s) Of Engagement Activity | 2018 |
| Description | Public lecture |
| 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 | Public/other audiences |
| Results and Impact | Public lecture on the genetics and biology of motor neuron disease |
| Year(s) Of Engagement Activity | 2016 |
| Description | Public lecture on motor neuron disease research |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Supporters |
| Results and Impact | I spoke at a dinner hosted by the MND Association for major donors at the Royal Institution |
| Year(s) Of Engagement Activity | 2016 |
| Description | Review of Dementia Research Institute at King's |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Talk on the Dementia Research activity at Kings |
| Year(s) Of Engagement Activity | 2018 |
| Description | School visit Peterborough |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | Schools |
| Results and Impact | Lectured to school students and informal chat Enthusiastic discussion |
| Year(s) Of Engagement Activity | 2006 |
| Description | Simon Topp's participation in MNDA fundraiser outreach - Promoting the research done at KCL in the field of Amyotrophic Lateral Sclerosis, to representatives from the UK's primary Motor Neurone Disease charity |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Supporters |
| Results and Impact | A group of fundraisers (primarily consisting of spouses, children, and friends of patients) from the Motor Neurone Disease Association charity visited KCL and met with researchers in small groups, with the aim of discovering more about the research work done here on MND (Amyotrophic Lateral Sclerosis). I gave a 10 minute presentation to 8 groups in succession on the use of Whole Exome Sequencing to discover new genes causative for MND/ALS, and highlighted how KCL had been closely involved in the discovery of 10 of the 45 genes identified to date, averaging over one per year for the last 6 years. This event was recent and as yet there has been no formal feedback, but responses on the day were very positive. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Sleep and circadian rhythm disorder in Parkinson's Disease: association with hallucinations |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | A world conference on sleep. Received a citation award. |
| Year(s) Of Engagement Activity | 2007 |
| Description | Talk at Dementia Discovery Fund Conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Industry/Business |
| Results and Impact | Presentation on opportunities for Gene Therapy in motor neuron disease and fronto-temporal dementia |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://theddfund.com/ |
| Description | Talk to MND Association of New Zealand annual general meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Public Presentation |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://mnd.org.nz/inaugural-mnd-new-zealand-research-conference/ |
| Description | The Use of Mass Spectrometry for Multi-site Phosphorylation Assays for Tau Protein |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Poster presentation at International Conference on Alzheimer's Disease, Chicago None |
| Year(s) Of Engagement Activity | 2008 |
| Description | Webinar on new therapies for Dementia Discovery Fund Forum |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Industry/Business |
| Results and Impact | Panel discussion on gene therapies for neurodegenerative disorders |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://issuu.com/svhealthinvestors/docs/ddf_20forum_20booklet_202020_2134dff6b56939 |