Investigation of the pathogenic basis of the tau gene association with neurodegeneration
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
The tau protein is an indispensable building block of a healthy nerve cell. Its main function is in the scaffolding network that supports the axons, the long, delicate processes that extend from the nerve cells. A healthy nerve cell requires a finely regulated supply of tau protein. It is now recognised that subtle variations within the tau gene and protein contribute to some movement disorders and dementias such as progressive supranuclear palsy (PSP) and Alzheimer s disease (AD). In recent work, we have used complex genetic analysis to pinpoint which regions of the tau gene contain such variations. We also have shown that their malign influence is by way of increasing production of the tau protein. With this project, we are using cellular and genetic models to investigate exactly how, within the context of the nerve cell, these genetic variations lead to the increased production of the tau protein. A better understanding of this could contribute towards the development of therapeutic approaches that, with greater precision, target the defective pathways. In the case of the tau gene, this could be by fine adjustment of tau protein production to the precise levels that a healthy nerve cell requires.
Technical Summary
Tauopathies are the class of neurodegenerative disorders characterised by pathological inclusions containing fibrillar deposits of the microtubule-associated protein, tau. The tau gene (MAPT) is mutated in frontotemporal dementia with parkinsonism with tau pathology linked to chromosome 17 (FTDP-17T) and, though not mutated, the H1 haplotype of MAPT is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and, to a lesser extent, with sporadic Parkinson?s disease (PD). We have succeeded in describing the full extent of the MAPT haplotype to a region of near complete linkage disequilibrium (LD) extending over about 1.8 million base pairs and have identified sub-haplotypes within this region, particularly in MAPT itself and MAPT promoter polymorphisms affecting the core promoter and putative conserved enhancer domains that are more associated with PSP, CBD and Alzheiimer s disease (AD). Furthermore, recent findings show that the extended LD of the MAPT region is caused by a large genomic inversion and this region is subject to further chromosomal rearrangements including deletions and multiplications. In this work, we propose a systematic approach to study the potential effects of the MAPT gene polymorphisms and the gross genomic rearrangements on the expression and splicing of MAPT and genes in flanking regions. We will map the inverted chromosomal region in order to identify any disease-specific, pathogenic configurations, including partial and complete deletion or multiplication of genes.
Organisations
- University College London, United Kingdom (Collaboration, Lead Research Organisation)
- Justus-Liebig University Giessen, Germany (Collaboration)
- University of Gothenburg, Sweden (Collaboration)
- Mayo Clinic (Collaboration)
- Eisai Ltd (Collaboration)
- Karolinska University Hospital (Collaboration)
- August Pi i Sunyer Biomedical Research Institute (Collaboration)
- Royal Free Hospital (Collaboration)
- Cardiff University, United Kingdom (Collaboration)
- University of Pennsylvania, United States (Collaboration)
- Eberhard Karls University Tuebingen, Germany (Collaboration)
- MRC Harwell, United Kingdom (Collaboration)
- Texas Technical University (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- Cure PSP (Foundation for PSP/CBD and Related Brain Diseases) (Collaboration)
- International Centre for Genetic Engineering and Biotechnology (Collaboration)
- University of Texas at San Antonio, United States (Collaboration)
- national Institute on Aging (Collaboration)
- Medical University of Vienna (Collaboration)
- Washington University in St Louis, United States (Collaboration)
- Philipps University of Marburg, Germany (Collaboration)
- Children's Hospital of Philadelphia (Collaboration)
- Brescia University Hospital (Collaboration)
- University of Zagreb (Collaboration)
- Sainsbury Research Unit (Collaboration)
- University of Pittsburgh (Collaboration)
Publications
Ahmed Z
(2011)
Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies.
in Acta neuropathologica
Anaya F
(2011)
Tau gene promoter rs242557 and allele-specific protein binding
in Translational Neuroscience
Babic Leko M
(2018)
Association of MAPT haplotype-tagging polymorphisms with cerebrospinal fluid biomarkers of Alzheimer's disease: A preliminary study in a Croatian cohort.
in Brain and behavior
Beck J
(2014)
Validation of next-generation sequencing technologies in genetic diagnosis of dementia.
in Neurobiology of aging
Bullmann T
(2007)
Expression of embryonic tau protein isoforms persist during adult neurogenesis in the hippocampus.
in Hippocampus
Compta Y
(2011)
Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?
in Brain : a journal of neurology
Connie L
(2010)
Brain tau isoform mRNA and protein correlation in PSP brain
in Translational Neuroscience
Counsell JR
(2018)
Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice.
in Molecular therapy. Nucleic acids
De Silva R
(2006)
An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies.
in Acta neuropathologica
Dickey C
(2009)
Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy.
in The American journal of pathology
| Description | ART Major Research Grant (Co-applicant) |
| Amount | £213,609 (GBP) |
| Funding ID | ART-PG2007-2 |
| Organisation | Alzheimer's Research UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2007 |
| End | 04/2011 |
| Description | ART PhD Studentship |
| Amount | £87,504 (GBP) |
| Organisation | Alzheimer's Research UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2007 |
| End | 09/2010 |
| Description | Collaborative research grant |
| Amount | 1,672,000 kr (SEK) |
| Organisation | CBD Solutions |
| Sector | Private |
| Country | Unknown |
| Start | 02/2016 |
| End | 02/2018 |
| Description | Cure PSP/Charles Peebler Foundation Genetics Consortium |
| Amount | £12,600 (GBP) |
| Organisation | Cure PSP (Foundation for PSP/CBD and Related Brain Diseases) |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 02/2009 |
| End | 01/2010 |
| Description | CurePSP Investigator Initiated Research Grant |
| Amount | $75,049 (USD) |
| Organisation | Cure PSP (Foundation for PSP/CBD and Related Brain Diseases) |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 12/2014 |
| End | 07/2016 |
| Description | Innovation Grant |
| Amount | £34,957 (GBP) |
| Funding ID | K-1212 |
| Organisation | Parkinson's UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2013 |
| End | 12/2013 |
| Description | International Joint Project |
| Amount | £11,271 (GBP) |
| Organisation | The Royal Society |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 01/2009 |
| End | 01/2011 |
| Description | PSP Association Research Grant |
| Amount | £43,180 (GBP) |
| Organisation | Progressive Supranuclear Palsy Association (PSPA) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 12/2014 |
| End | 06/2016 |
| Description | Peacock Trust Research Grant |
| Amount | £75,000 (GBP) |
| Organisation | Peacock Charitable Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2009 |
| End | 01/2011 |
| Description | PhD Studentship |
| Amount | £72,000 (GBP) |
| Organisation | Age UK |
| Department | Research into Ageing Fund (RiAF) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2009 |
| End | 10/2012 |
| Description | Research Grant |
| Amount | £172,193 (GBP) |
| Organisation | CBD Solutions |
| Sector | Private |
| Country | Unknown |
| Start | 03/2017 |
| End | 02/2018 |
| Description | Research Grant |
| Amount | £204,308 (GBP) |
| Organisation | CBD Solutions |
| Sector | Private |
| Country | Unknown |
| Start | 07/2018 |
| End | 12/2019 |
| Description | The Irene & Abe Pollin Fund for CBD Research |
| Amount | £126,200 (GBP) |
| Organisation | Cure PSP (Foundation for PSP/CBD and Related Brain Diseases) |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 06/2010 |
| End | 05/2012 |
| Title | AAV Vectors for CNS expression |
| Description | Investigation of the therapeutic potential of reduction of tau protein in CNS using truncated long non-coding RNA linked to the tau gene. Derivation of AAV9 vectors for CNS delivery of the long non-coding RNAs |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2018 |
| Provided To Others? | No |
| Impact | Project in progress. Current outcome: Wide CNS distribution after AAV9 injection in mouse model with reduction in brain levels of tau. We expect accompanying therapeutic effect. |
| Title | Assays for total tau and tau isoform quantitation in brain and CSF |
| Description | Based on monoclonal antibodies that we developed that recognise the three- and four-repeat isoforms of the tau protein, we have developed ELISA-based platforms for the sensitive measurement of these tau isoforms in brain and CSF. Disturbances in homeostasis of these two isoforms are a central pathogenic mechanism in many of the tauopathies. Early detection of these changes may be important in development of therapies. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2012 |
| Provided To Others? | Yes |
| Impact | The first assays available for measuring brain and CSF tau isoforms. |
| Title | Bi-cistronic reporter vector for investigation of tau gene promoter activity |
| Description | Bi-cistronic vector allows investigation of CAP- and/or IRES-dependent expression of the tau gene and assess role of non-coding RNA genes and stressors on steering this expression |
| Type Of Material | Model of mechanisms or symptoms - in vitro |
| Year Produced | 2017 |
| Provided To Others? | No |
| Impact | As with stable cell lines for non-coding RNA genes, these constructs have allowed us dissect the role of non-coding RNAs in tau gene expression. |
| Title | Brain expression database |
| Description | Array-based genomewide expression data from 10 regions of 140 control brains together with genomewide genotype data (UK Brain Expression Consortium) |
| Type Of Material | Biological samples |
| Year Produced | 2013 |
| Provided To Others? | Yes |
| Impact | Publications: 23408064, 23967090, 22723018, 25174004, 24503276 |
| URL | http://ukbec.wordpress.com/ |
| Title | PSP genetic data |
| Description | Genotype data for tau gene in pathologically confirmed PSP cases from the London Queen Square Brain Bank and Mayo Clinic PSP brain bank and appropriate controls. Genomewide genotype data based on Illumina 660K array for all abovementioned PSP cases. |
| Type Of Material | Biological samples |
| Year Produced | 2010 |
| Provided To Others? | Yes |
| Impact | Identification of possible functional basis of an association of the tau gene with PSP and CBD. Identification of other loci genomewide that are associated with PSP implicating novel pathways |
| Title | Stable cell lines for tau gene associated non-coding RNA genes |
| Description | Stable overexpression of non-coding RNA genes enables consistent cell-based model to investigate the downstream regulatory effects of these non-coding genes |
| Type Of Material | Model of mechanisms or symptoms - in vitro |
| Year Produced | 2015 |
| Provided To Others? | No |
| Impact | Have succeeded in clarifying the precise role of the non-coding RNA genes in the post-transcriptional regulation of tau gene expression |
| Title | Stably expressing tau and alpha-synuclein cell lines |
| Description | Clonal neuroblastoma cell lines expressing wild-type and mutant alpha-synuclein and tau isoforms |
| Type Of Material | Cell line |
| Year Produced | 2012 |
| Provided To Others? | Yes |
| Impact | Publications (24521289, 22039514 and Marta Swirski, J Scott Miners, Rohan de Silva, Tammaryn Lashley, Helen Ling, Janice Holton, Tamas Revesz and Seth Love (2014) Evaluating the relationship between amyloid-beta and alpha-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson's disease; Alzheimer's Research & Therapy) and successful PhD studentship grant |
| Title | Tau gene allele-specific promoter activity assays in cell culture |
| Description | The core promoter and putative conserved enhancer regions of the tau gene promoter have been cloned into a luciferase reporter vector in order to assess the allele-specific differences in promoter polymorphisms that confer disease risk. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2012 |
| Provided To Others? | Yes |
| Impact | We have shown that increased risk of sporadic tauopathies is caused by significantly increased levels of tau gene transcription. This research material could be used for testing approaches to reduce tau transcription as a potential therapy. |
| Title | UK Brain Expression Database |
| Description | Genomewide exon array expression data from 10 regions of 100 healthy control brains |
| Type Of Material | Database/Collection of data |
| Year Produced | 2013 |
| Provided To Others? | Yes |
| Impact | Public availability of data, resource paper (PMID: 25174004) and several publications (internal and external) (please see: http://www.ncbi.nlm.nih.gov/pubmed/?term=ryten+and+weale) |
| URL | http://www.braineac.org |
| Description | A cell model for exosomal release of tau |
| Organisation | Royal Free Hospital |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | I have provided tau cell lines and tau antibodies that will form the core of this project to investigate chaperone mediated autophagy exosomal release of tau as well as intellectual input and co-supervision of PhD student |
| Collaborator Contribution | They are carrying out the laboratory investigations of the cell lines and have also secured the PhD studentship starting in Spring 2015. |
| Impact | Early stage in research as part of a studentship from Alzheimer's Society UK. PhD successfully completed in 2018. |
| Start Year | 2013 |
| Description | CBD clinicopathological classification |
| Organisation | University College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of team to investigate clinico-pathological correlates in progression of corticobasal degeneration and pathological seeding species. Participating with expert input into project and assisting in experimental procedures. |
| Collaborator Contribution | They have described markers of clinico-pathological progression of tauopathy in corticobasal degeneration (CBD) and obtained funding for neuropathological classification of CBD sub-types and established methodology to investigate pathological seeding and spread in postmortem material. |
| Impact | Ongoing. |
| Start Year | 2017 |
| Description | CSF biomarkers for differential diagnosis of PSP clinical sub-types |
| Organisation | Eberhard Karls University of Tubingen |
| Department | Centre of Neurology and Hertie-Institute for Clinical Brain Research |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Developed sensitive assays for quantitation of tau variants in CSF |
| Collaborator Contribution | Patient samples and intellectual contribution |
| Impact | None yet |
| Start Year | 2011 |
| Description | Identification of genetic cause of frontotemporal dementia in a population isolate |
| Organisation | Brescia University Hospital |
| Department | Neurology Clinic |
| Country | Italy |
| Sector | Hospitals |
| PI Contribution | Genomewide autozygosity analysis to identify any regions of homozygosity. Exome sequencing of affected individuals |
| Collaborator Contribution | DNA samples from affected cases. Clinical classificationThey have contributed key bioinformatics expertise |
| Impact | Genomewide screening completed. Analysis in progress Poster presented at SINDEM meeting in Florence, Italy, 2010. Analysis of exome data pending |
| Start Year | 2009 |
| Description | Identification of genetic cause of frontotemporal dementia in a population isolate |
| Organisation | University College London |
| Department | Institute of Neurology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Genomewide autozygosity analysis to identify any regions of homozygosity. Exome sequencing of affected individuals |
| Collaborator Contribution | DNA samples from affected cases. Clinical classificationThey have contributed key bioinformatics expertise |
| Impact | Genomewide screening completed. Analysis in progress Poster presented at SINDEM meeting in Florence, Italy, 2010. Analysis of exome data pending |
| Start Year | 2009 |
| Description | Loukia |
| Organisation | Sainsbury Research Unit |
| Country | Unknown |
| Sector | Academic/University |
| PI Contribution | Expertise, methodology and materials |
| Collaborator Contribution | Expertise on behavioural models and pathological progression. |
| Impact | None yet (ongoing) |
| Start Year | 2018 |
| Description | MAPT in PSP clinical sub-types |
| Organisation | University College London |
| Department | Institute of Neurology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Analysed genetic association of tau gene haplotypes in PSP clinical sub-types, including Richardson's Syndrome, PSP-parkinsonism. |
| Collaborator Contribution | Contributed patient clinical, neuropathological and biochemical data |
| Impact | 17274033 17525140 23432126 Multidisciplinary: Clinical, Genetics, Neuropathology, Biochemistry |
| Start Year | 2006 |
| Description | Neuropathology and genetics of tauopathies |
| Organisation | University of Zagreb |
| Department | Croatian Institute for Brain Research |
| Country | Croatia |
| Sector | Academic/University |
| PI Contribution | Screening tau gene haplotypes of clinical dementia cases and contributed tau isoform-specific antibodies and intellectual input |
| Collaborator Contribution | Provided and classified local postmortem patient material |
| Impact | 30329219, 27084356, 26751493 |
| Start Year | 2006 |
| Description | PSP Genomewide Association Study Consortium |
| Organisation | Children's Hospital of Philadelphia |
| Department | Center for Applied Genomics |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Contributed pathologically confirmed and clinical cases for genomewide analysis. Founder member of core steering group in consortium. |
| Collaborator Contribution | Patient samplesIntellectual, sample and clinical contributionConsortium leader, sample and intellectual contribution, microarray and data analysisData Analysis, Intellectual contributionData analysis and intellectual contributionSample contribution, intellectual contributionFunded and coordinated consortium |
| Impact | 21685912, 24252572 Genomewide screening and analysis completed with the identification of multiple genes that are genomewide significant. Novel pathways implicated in PSP pathogenesis. Results presented at ICAD, Honolulu, 2010 and International PSP Workshop, San Diego, 2010. Work published in Nature Genetics. |
| Start Year | 2007 |
| Description | PSP Genomewide Association Study Consortium |
| Organisation | Cure PSP (Foundation for PSP/CBD and Related Brain Diseases) |
| Department | Peebler Foundation PSP Genetics Programme |
| Country | United States |
| Sector | Charity/Non Profit |
| PI Contribution | Contributed pathologically confirmed and clinical cases for genomewide analysis. Founder member of core steering group in consortium. |
| Collaborator Contribution | Patient samplesIntellectual, sample and clinical contributionConsortium leader, sample and intellectual contribution, microarray and data analysisData Analysis, Intellectual contributionData analysis and intellectual contributionSample contribution, intellectual contributionFunded and coordinated consortium |
| Impact | 21685912, 24252572 Genomewide screening and analysis completed with the identification of multiple genes that are genomewide significant. Novel pathways implicated in PSP pathogenesis. Results presented at ICAD, Honolulu, 2010 and International PSP Workshop, San Diego, 2010. Work published in Nature Genetics. |
| Start Year | 2007 |
| Description | PSP Genomewide Association Study Consortium |
| Organisation | Justus Liebig University Giessen |
| Department | Institute of Human Genetics |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Contributed pathologically confirmed and clinical cases for genomewide analysis. Founder member of core steering group in consortium. |
| Collaborator Contribution | Patient samplesIntellectual, sample and clinical contributionConsortium leader, sample and intellectual contribution, microarray and data analysisData Analysis, Intellectual contributionData analysis and intellectual contributionSample contribution, intellectual contributionFunded and coordinated consortium |
| Impact | 21685912, 24252572 Genomewide screening and analysis completed with the identification of multiple genes that are genomewide significant. Novel pathways implicated in PSP pathogenesis. Results presented at ICAD, Honolulu, 2010 and International PSP Workshop, San Diego, 2010. Work published in Nature Genetics. |
| Start Year | 2007 |
| Description | PSP Genomewide Association Study Consortium |
| Organisation | Mayo Clinic |
| Country | United States |
| Sector | Charity/Non Profit |
| PI Contribution | Contributed pathologically confirmed and clinical cases for genomewide analysis. Founder member of core steering group in consortium. |
| Collaborator Contribution | Patient samplesIntellectual, sample and clinical contributionConsortium leader, sample and intellectual contribution, microarray and data analysisData Analysis, Intellectual contributionData analysis and intellectual contributionSample contribution, intellectual contributionFunded and coordinated consortium |
| Impact | 21685912, 24252572 Genomewide screening and analysis completed with the identification of multiple genes that are genomewide significant. Novel pathways implicated in PSP pathogenesis. Results presented at ICAD, Honolulu, 2010 and International PSP Workshop, San Diego, 2010. Work published in Nature Genetics. |
| Start Year | 2007 |
| Description | PSP Genomewide Association Study Consortium |
| Organisation | Philipp University of Marburg |
| Department | Department of Neurology |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Contributed pathologically confirmed and clinical cases for genomewide analysis. Founder member of core steering group in consortium. |
| Collaborator Contribution | Patient samplesIntellectual, sample and clinical contributionConsortium leader, sample and intellectual contribution, microarray and data analysisData Analysis, Intellectual contributionData analysis and intellectual contributionSample contribution, intellectual contributionFunded and coordinated consortium |
| Impact | 21685912, 24252572 Genomewide screening and analysis completed with the identification of multiple genes that are genomewide significant. Novel pathways implicated in PSP pathogenesis. Results presented at ICAD, Honolulu, 2010 and International PSP Workshop, San Diego, 2010. Work published in Nature Genetics. |
| Start Year | 2007 |
| Description | PSP Genomewide Association Study Consortium |
| Organisation | University of Pennsylvania |
| Department | Perelman School of Medicine |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Contributed pathologically confirmed and clinical cases for genomewide analysis. Founder member of core steering group in consortium. |
| Collaborator Contribution | Patient samplesIntellectual, sample and clinical contributionConsortium leader, sample and intellectual contribution, microarray and data analysisData Analysis, Intellectual contributionData analysis and intellectual contributionSample contribution, intellectual contributionFunded and coordinated consortium |
| Impact | 21685912, 24252572 Genomewide screening and analysis completed with the identification of multiple genes that are genomewide significant. Novel pathways implicated in PSP pathogenesis. Results presented at ICAD, Honolulu, 2010 and International PSP Workshop, San Diego, 2010. Work published in Nature Genetics. |
| Start Year | 2007 |
| Description | PSP Genomewide Association Study Consortium |
| Organisation | University of Pittsburgh |
| Department | School of Medicine Pittsburgh |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Contributed pathologically confirmed and clinical cases for genomewide analysis. Founder member of core steering group in consortium. |
| Collaborator Contribution | Patient samplesIntellectual, sample and clinical contributionConsortium leader, sample and intellectual contribution, microarray and data analysisData Analysis, Intellectual contributionData analysis and intellectual contributionSample contribution, intellectual contributionFunded and coordinated consortium |
| Impact | 21685912, 24252572 Genomewide screening and analysis completed with the identification of multiple genes that are genomewide significant. Novel pathways implicated in PSP pathogenesis. Results presented at ICAD, Honolulu, 2010 and International PSP Workshop, San Diego, 2010. Work published in Nature Genetics. |
| Start Year | 2007 |
| Description | Regional expression QTLs of tau in human brain |
| Organisation | Cardiff University |
| Department | School of Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Contributed and prepared patient postmortem samples and carried out some of the gene expression analysis and intellectual input |
| Collaborator Contribution | Did bulk of analysis |
| Impact | 23428180 Multidisciplinary: Clinical, Genetic, biochemistry |
| Start Year | 2010 |
| Description | Simon-Raj In vivo work |
| Organisation | University College London |
| Department | Institute for Women's Health |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Indentification and characterisation of tau gene promoter associated long-non-coding RNA gene involved in regulation of tau gene. Design of active minimised variants and derivation of AAV expression vectors for in vivo work |
| Collaborator Contribution | Maintenance of mouse colony, AAV injection and behavioural studies |
| Impact | Ongoing. One publication has resulted from collaboration (PMID: 30081233) |
| Start Year | 2016 |
| Description | Stephanie-Seizures |
| Organisation | University College London |
| Department | Department of Clinical and Experimental Epilepsy |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Identification and characterisation of long non-coding RNA gene linked to the tau gene that is involved in regulation of tau gene expression. Characterised functional domains and derived truncated active variant. Raised AAV vectors for expression of variants in vivo |
| Collaborator Contribution | Maintenance of mouse colony. Assessment of experimentally induced epileptic seizures and affect of tau reduction due to injection of AAV vectors. |
| Impact | In progress - no outcomes |
| Start Year | 2016 |
| Description | Study of MAPT in PSP |
| Organisation | National Institute on Aging |
| Country | United States |
| Sector | Public |
| PI Contribution | Mapped MAPT gene in PSP and established in vitro luciferase assay for allele-specific gene expression studies. |
| Collaborator Contribution | Use of high-throughput genotyping technology and intellectual contributions to successful projects |
| Impact | 16493238 17174556 Multidisciplinary: Clinical, Genetics, Cell Biology, Neuropathology |
| Start Year | 2006 |
| Description | TDP43 and tau expression |
| Organisation | International Centre for Genetic Engineering and Biotechnology |
| Country | Italy |
| Sector | Charity/Non Profit |
| PI Contribution | We initiated the project and are responsible for planning and carrying out the bulk of the work. |
| Collaborator Contribution | Intellectual contributionIntellectual contribution and access to research reagents developed by groupExchange of research reagents and tools |
| Impact | In collaboration we have shown that TDP43 has a key effect on the regulation of tau gene expression. |
| Start Year | 2009 |
| Description | TDP43 and tau expression |
| Organisation | MRC Harwell |
| Department | MRC Mammalian Genetics Unit |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | We initiated the project and are responsible for planning and carrying out the bulk of the work. |
| Collaborator Contribution | Intellectual contributionIntellectual contribution and access to research reagents developed by groupExchange of research reagents and tools |
| Impact | In collaboration we have shown that TDP43 has a key effect on the regulation of tau gene expression. |
| Start Year | 2009 |
| Description | TDP43 and tau expression |
| Organisation | University College London |
| Department | Institute of Neurology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We initiated the project and are responsible for planning and carrying out the bulk of the work. |
| Collaborator Contribution | Intellectual contributionIntellectual contribution and access to research reagents developed by groupExchange of research reagents and tools |
| Impact | In collaboration we have shown that TDP43 has a key effect on the regulation of tau gene expression. |
| Start Year | 2009 |
| Description | Tau genetics and pathology in PD with dementia |
| Organisation | August Pi i Sunyer Biomedical Research Institute |
| Department | Hospital Clinic of Barcelona |
| Country | Spain |
| Sector | Hospitals |
| PI Contribution | Collaborator was the primary person involved in the project and collated/analysed clinical, pathological and genetic data for PD cases at the Queen Square Brain Bank, London |
| Collaborator Contribution | Intellectual contribution |
| Impact | 21596773 Neuropathological correlates to PD with and without dementia established Published in Brain |
| Start Year | 2009 |
| Description | Tau in Parkinson's disease |
| Organisation | University College London |
| Department | Institute of Neurology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Screened tagging SNPs for tau gene region in sporadic Parkinson's disease cases. |
| Collaborator Contribution | Intellectual contribution |
| Impact | 18162161, 23408064, 21738488 Multidisciplinary: Genetics, Clinical |
| Start Year | 2006 |
| Description | Tau locus deletions and developmental delay |
| Organisation | The Wellcome Trust Sanger Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | Mapped MAPT gene region for large deletion that causes developmental delay and facial dysmorphia in young children |
| Collaborator Contribution | Provided patient material and initial data |
| Impact | 16906163 Multidisciplinary: Clinical, Genetics |
| Start Year | 2006 |
| Description | Tau mutation screening |
| Organisation | Medical University of Vienna |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | Sequenced patient DNA for tau mutations and carried out splicing study and protein analysis |
| Collaborator Contribution | Contributed patient DNA and brain samples as well as clinical description |
| Impact | 18066559 Multidisciplinary: Clinical, Genetics, Biochemistry, Neuropathology |
| Start Year | 2007 |
| Description | Tau mutation screening in tauopathy |
| Organisation | National Institute on Aging |
| Country | United States |
| Sector | Public |
| PI Contribution | Sequenced tau gene and identified tau gene deletion - investigated effect of deletion on tau gene splicing |
| Collaborator Contribution | Contributed patient DNA and brain sample and clinical data.Exchanged patient samples, carrying out candidate gene sequencing, exchange of lab personnel. |
| Impact | 17723255 Multidisciplinary: Clinical, Genetics, Biochemistry, Neuropathology |
| Start Year | 2007 |
| Description | Tau mutation screening in tauopathy |
| Organisation | Texas Tech University |
| Department | Department of Internal Medicine |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Sequenced tau gene and identified tau gene deletion - investigated effect of deletion on tau gene splicing |
| Collaborator Contribution | Contributed patient DNA and brain sample and clinical data.Exchanged patient samples, carrying out candidate gene sequencing, exchange of lab personnel. |
| Impact | 17723255 Multidisciplinary: Clinical, Genetics, Biochemistry, Neuropathology |
| Start Year | 2007 |
| Description | Tau mutation screening in tauopathy cases |
| Organisation | University College London |
| Department | Institute of Neurology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Sequenced tauopathy cases and identified causative mutations. |
| Collaborator Contribution | Provided clinical patient samples and clinical data |
| Impact | 19884572, 20838030, 23998997, 22595371 Multidisciplinary: Clinical, Genetics, Biochemistry, Neuropathology |
| Start Year | 2008 |
| Description | Tau mutation screening in tauopathy cases |
| Organisation | University College London |
| Department | MRC Prion Unit |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | Sequenced tauopathy cases and identified causative mutations. |
| Collaborator Contribution | Provided clinical patient samples and clinical data |
| Impact | 19884572, 20838030, 23998997, 22595371 Multidisciplinary: Clinical, Genetics, Biochemistry, Neuropathology |
| Start Year | 2008 |
| Description | Tau oligomers in neurodegeneration |
| Organisation | University of Texas |
| Department | Mitchell Centre for Neurodegenerative Diseases |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Provided patient samples and am assessing tau-oligomer specific antibodies from partner on brain tissue. Studying release and intercellular spread of tau oligomer species. |
| Collaborator Contribution | Provided oligomer-specific antibodies and assaying oligomer levels in patient CSF samples |
| Impact | Ongoing |
| Start Year | 2012 |
| Description | Tau-based diagnostic biomarkers in CSF |
| Organisation | University of Gothenburg |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Developed sensitive assays for detection of tau variants as biomarkers in CSF in neurodegenerative disorders |
| Collaborator Contribution | Contributed patient CSF samples and intellectual input |
| Impact | 22862741 Clinical, biochemistry, clinical diagnostics |
| Start Year | 2010 |
| Description | Tau-based gene therapy for neurodegenerative disorders |
| Organisation | Karolinska University Hospital |
| Department | Center for Molecular Medicine |
| Country | Sweden |
| Sector | Hospitals |
| PI Contribution | We have developed vectors to test the concept of gene therapy directed at tau gene expression in slowing or halting the progress of tau-relaed neurodegeneration. |
| Collaborator Contribution | Injection and study of mouse models for tauopathy |
| Impact | None to date - still in progress |
| Start Year | 2015 |
| Description | Tau-based therapies in tauopathies |
| Organisation | Eisai Ltd |
| Country | Japan |
| Sector | Private |
| PI Contribution | Based on our research findings and reagents developed, I have led a collaboration to develop a passive immunotherapy for tauopathies and small molecule screening for regulating tau gene expression. I have provided relevant antibodies and a cell culture model for high-throughput screening. I meet regularly with partners at Eisai in planning meetings and provide intellectual input |
| Collaborator Contribution | Facilitating collaboration by testing antibodies and proposing ways of improving antibody affinity. Ongoing collaboration as part of UCL-Eisai Therapeutic Innovation Group (TIG), we have developed a new, more effective antibody for tau-targeted passive immunotherapy and humanised version will be entering clinical trials in April 2019. |
| Impact | We developed cell-based system for quantification of tau aggregation and anti-aggregation properties of new antibodies. We have also developed TWELVE new antibodies of which one (E2814) will be entered into clinical trials in Alzheimer's disease. |
| Start Year | 2012 |
| Description | WUSTL CRISPR |
| Organisation | Washington University in St Louis |
| Department | Hope Center for Neurological Disorders |
| Country | United States |
| Sector | Charity/Non Profit |
| PI Contribution | We identified crucial polymprphisms in the tau gene promoter and a non-coding RNA gene overlapping with the tau gene promoter that regulates expression, including identification of the essential elements of the non-coding RNA gene. |
| Collaborator Contribution | Partners are helping us gene edit by CRISPR the tau gene promoter polymorphisms and deactivation of the essential elements of the non-coding RNA gene to confirm functionality |
| Impact | Collaboration terminated |
| Start Year | 2016 |
| Title | MEANS FOR MODULATING GENE EXPRESSION |
| Description | The use of coding-gene linked long-non-coding RNA gene transcripts for transcriptional regulation of gene expression - as a therapeutic or research tool. |
| IP Reference | GB1608907.0 |
| Protection | Patent application published |
| Year Protection Granted | 2016 |
| Licensed | No |
| Impact | Collaborations to test concept in vivo and approach by potential investors to for spin out company. |
| Title | Tau isoform-specific monoclonal antibodies |
| Description | Imbalances in the tau 3R and 4R isoforms are an important cause of many of the common neurological disorders of old age. The two antibodies recognise 3R and 4R tau and are now routinely used in pathological diagnosis of neurological disorders, research studies of animal models of neurological disorders and in biochemistry of neurological disorders. |
| IP Reference | |
| Protection | Protection not required |
| Year Protection Granted | |
| Licensed | Yes |
| Impact | These antibodies have provided the basis for sandwich ELISA for quantitation of tau isoforms in tissue (PMID: 19427527) and more sensitive immuno-PCR assays for quantitation of tau isoforms in cerebrospinal fluid (PMID: 22862741). Our initial validation study in clinical CSF samples suggest diagnostically relevant differences in tau isoforms in tauopathies. |
| Title | Assays for CSF tau |
| Description | Disturbances in tau isoform homeostasis are an important pathogenic mechanism in several progressive neurodegenerative disorders. Based on antibodies that recognise tau isoforms we have developed a sandwich ELISA that enables us to measure these isoforms in human tissue. In addition, we have developed a more sensitive Immuno-PCR assay (IPCR) to quantify tau isoforms in CSF. We have completed measurements of CSF tau isoforms in large collections of clinical CSFs and are currently analysing the data. Most recent funding was from the Brain Research Trust. However this funding is over and we seek further funding as well as collaborations with industry. |
| Type | Diagnostic Tool - Non-Imaging |
| Current Stage Of Development | Refinement. Clinical |
| Year Development Stage Completed | 2010 |
| Development Status | Actively seeking support |
| Impact | These are the first assays that enable us to measure tau isoforms in human tissue and CSF. Due to disturbances in the homeostasis of these isoforms causing disease, we believe that these assays could serve as a diagnostic tool and to identify pre-clinical cases. We are currently using the IPCR to measure tau isoforms in a large collection of disease CSFs from various centres in Europe to see if it has any diagnostic value. |
| Title | RNA based therapy |
| Description | We identified specific RNAs that modulate tau gene expression. We have completed testing in cell models. Current and most recent funding: PDUK |
| Type | Therapeutic Intervention - Cellular and gene therapies |
| Current Stage Of Development | Refinement. Non-clinical |
| Year Development Stage Completed | 2013 |
| Development Status | Actively seeking support |
| Impact | Very specific reduction of tau gene expression in cell models. Other work suggests that reduction of tau levels could be an effective therapy in neurodegenerative tauopathies. |
| Title | lncRNAs and therapeutic reduction of tau |
| Description | Refined/truncated lncRNA transcript delivery in vivo by AAV vectors to test if tau is reduced and if there is any therapeutic benefits in animal models of tauopathies. Most recent funding from Brain Research Trust. |
| Type | Therapeutic Intervention - Cellular and gene therapies |
| Current Stage Of Development | Refinement. Non-clinical |
| Year Development Stage Completed | 2016 |
| Development Status | Under active development/distribution |
| Impact | Possibly using the same concept to regulate translation of other genes |
| Description | Age UK brochure entry |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | Yes |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Lay summary of my research together with its importance outlined in brochure for distribution to potential donors to Age UK. Too early to judge impact |
| Year(s) Of Engagement Activity | 2010 |
| Description | Brain Bank Newsletter |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Wrote lay article for Queen Sq Brain Bank Newsletter that was distributed among patient groups, families, carers and medical practitioners. |
| Year(s) Of Engagement Activity | 2016 |
| Description | London Support Group - PSP Association |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Research lay update to local patient/carer support group Conveyed latest research findings and described prospect of treatments |
| Year(s) Of Engagement Activity | 2008 |
| Description | PSP Association Newsletter |
| 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 | Contributed lay research updates to quarterly "PSP Matters" magazine published by the PSP Association Better awareness |
| Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010 |
| Description | Queen Sq Brain Bank brochure |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Type Of Presentation | Paper Presentation |
| Geographic Reach | National |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Magazine for charity (PSP Association) with my articles in layspeak was distributed to patients and interest groups Greater awareness of charity funded research |
| Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010 |
| Description | Research Update PSP Association Trustees |
| 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 | Provided lay update on research and successfully made case for further funding for the development of a sensitive assay for quantification of tau in cerebrospinal fluid Successfully obtained funding for a further year. |
| Year(s) Of Engagement Activity | 2008 |
| Description | Research for Later Life Conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Attended by a mix of researchers and age welfare interest groups - role of tau in neurodegeneration and potential for therapies discussed n/a |
| Year(s) Of Engagement Activity | 2010 |
| Description | Reta Lila Weston Institute Research Report |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Book describing research output of Institute to the lay person. Contributed article on our research Just published. |
| Year(s) Of Engagement Activity | 2011,2012,2013,2014 |
| Description | Symposium for Carers and Therapists |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | National |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Gave lay research update to patients and carers in the form of a seminar. Caused greater interest in genetic impact of PSP |
| Year(s) Of Engagement Activity | 2006 |