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.

Publications

10 25 50
 
Description ART Major Research Grant (Co-applicant)
Amount £213,609 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
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 of Great Britain & Northern Ireland (UK)
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 of America
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 of America
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 of Great Britain & Northern Ireland (UK)
Start 01/2013 
End 12/2013
 
Description International Joint Project
Amount £11,271 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
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 of Great Britain & Northern Ireland (UK)
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 of Great Britain & Northern Ireland (UK)
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 of Great Britain & Northern Ireland (UK)
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 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 of America
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 
Provided To Others? No  
Impact Project in progress. Expected outcome: Wide CNS distribution after AAV9 injection in mouse model with reduction in brain levels of tau and accompanying therapeutic effect. 
 
Title Assays for 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 
Provided To Others? No  
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 
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 
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 
Provided To Others? No  
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 of Great Britain & Northern Ireland (UK) 
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 but we have secured a studentship from Alzheimer's Society UK.
Start Year 2013
 
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, Federal Republic of 
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, Italian Republic 
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 of Great Britain & Northern Ireland (UK) 
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 MAPT in PSP clinical sub-types 
Organisation University College London
Department Institute of Neurology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
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, Republic of 
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 Ongoing
Start Year 2006
 
Description PSP Genomewide Association Study Consortium 
Organisation Children's Hospital of Philadelphia
Department Center for Applied Genomics
Country United States of America 
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 of America 
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, Federal Republic of 
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 of America 
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, Federal Republic of 
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 of America 
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 of America 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 No outputs - in progress
Start Year 2016
 
Description Stephanie-Seizures 
Organisation University College London
Department Department of Clinical and Experimental Epilepsy
Country United Kingdom of Great Britain & Northern Ireland (UK) 
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 of America 
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, Italian Republic 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 (IDIBAPS)
Department Hospital Clinic of Barcelona
Country Spain, Kingdom of 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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, Republic of 
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 of America 
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 of America 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 of America 
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, Kingdom of 
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, Kingdom of 
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 proposed 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) in developing new, more effective antibodies for tau-targeted passive immunotherapy
Impact We have developed cell-based system for quantification of tau aggregation and anti-aggregation properties of new antibodies. We have also developed TWELVE new antibodies that are currently being subject to testing and, ultimately, target validation.
Start Year 2012
 
Description WUSTL CRISPR 
Organisation Columbia University
Department Department of Biomedical Engineering
Country United States of America 
Sector Academic/University 
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 In progress
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 1608907.0 
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