DISC1 complex: Neurosignalling and genetics

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Molecular Medicine

Abstract

Bipolar affective disorder and schizophrenia are severe and debilitating forms of mental illness that together affect up to one in fifty persons at some point in their life. These illnesses tend to cluster in families. This and other evidence points to genetic (inherited) factors being important. Recently, we identified one such factor, called Disrupted in Schizophrenia 1, or DISC1 for short. There is now a lot of support from many studies for this being an important risk factor not just in schizophrenia, but also bipolar disorder and depression. Recently, we identified another risk factor gene called PDE4B. PDE4B was already thought to be important in building memories in the brain. It does so by regulating the amount of a molecule called cAMP, the level of which is key to many brain processes. It turns out that DISC1 acts as a kind of master organiser not just of PDE4 but also other proteins that are believed to be important for how the brain develops, and processes sensory information. Our research is aimed at understanding these complex processes in more detail, to understand what makes them go wrong in persons with mental illness, with the long term hope that this knowledge and understanding may bring us closer to better treatments for these devastating illnesses. In the process, we also expect to reach a fuller understanding of how the brain normally develops, and of how the mind works.

Technical Summary

Schizophrenia (SZ) and Bipolar disorder (BP) are both in the WHO top ten estimates for disease related lifetime disability. Jointly, they have a lifetime incidence of about 2%. Both have strong genetic components, but until recently few genetic findings were consistently replicated. In 2000, we positionally cloned a completely novel gene, Disrupted in Schizophrenia 1, identified at one breakpoint of a balanced translocation that segregates with schizophrenia, bipolar affective disorder and recurrent major depression in a large Scottish family. Growing evidence from a wide range of study designs (linkage, association, and gene resequencing) finds broad support to link genetic variation in DISC1 to risk of SZ, BP and related major mental illness. The importance of DISC1 is further supported by the strong emerging evidence for the biological function of DISC1. DISC1 is a scaffold protein which interacts with multiple protein partners involved in neurodevelopment, cytoskeletal function and cell signalling. In 2005, we demonstrated that DISC1 interacts dynamically with phosphodiesterase 4B (PDE4B) to modulate cAMP, a key neuronal signalling molecule. We and others have early, but persuasive evidence for a role of DISC1 at the centrosome, at the synapse and in neurogenesis. A core complex of the proteins DISC1/PDE4/NDEL1/NDE1 is likely to be involved in these processes, each of which has an independent or co-dependent effect of genetic risk. Thus, the DISC1 complex is arguably the most promising biological pathway underpinning SZ and BP, a promising target for novel drug development and a route to understanding key aspects of brain development, learning and memory.

In this proposal we will address two inter-related questions:
1)What defines the DISC1 complex and how is it regulated?
2)How does the DISC1 complex impact on neurosignalling?
These two objectives will be integrated and informed by a third cross-cutting theme:
3)What is the effect of pathogenic mutations on DISC1 complex function?

To this end, we will build upon our now extensive biological resources, assays and techniques to test our hypotheses in cultured cells and primary neurons derived from normal and DISC1 mutant mouse models. At the end of this research grant we expect to have made significant inroads into the overarching question of the nature, regulation and function of the DISC1 complex and the impact of genetic variation.

Publications

10 25 50

publication icon
Bradshaw NJ (2011) PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Brandon NJ (2009) Understanding the role of DISC1 in psychiatric disease and during normal development. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description European Commision FP7
Amount € 3,918,138 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start  
 
Description IGMM studentship
Amount £121,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 08/2016
 
Description MRC project grant
Amount £479,301 (GBP)
Funding ID MR/J004367/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2012 
End 05/2015
 
Description Pfizer
Amount £397,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 11/2010 
End 04/2012
 
Description Wellcome Trust 4 year PhD studentship
Amount £141,634 (GBP)
Funding ID 083210 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2007 
End 08/2011
 
Description Wellcome Trust Project Grant
Amount £326,553 (GBP)
Funding ID WT088179MA 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2009 
End 05/2012
 
Description Young Investigator Award
Amount $30,777 (USD)
Funding ID 23306 
Organisation Brain & Behaviour Research Foundation 
Sector Charity/Non Profit
Country United States
Start 09/2015 
End 09/2017
 
Title DISC1 antibodies 
Description antibody specific to human DISC1 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact We have provided this material to many laboratories over a number of years. It is still under investigation. 
 
Title NDE1 antibody 
Description An antibody that specifically recognises human NDE1, without detection of the highly similar species NDEL1. 
Type Of Material Antibody 
Year Produced 2011 
Provided To Others? Yes  
Impact It is difficult to distinguish the highly similar NDE1 and NDEL1 proteins and it was initially believed that they perform identical functions. Specific antibodies such as this one are helping to demonstrate distinct expression patterns and functions. 
 
Title NDE1/NDEL1 pT131 
Description A phospho-specific antibody raised to a PKA site that modulates protein-protein interactions. 
Type Of Material Antibody 
Year Produced 2011 
Provided To Others? Yes  
Impact This antibody detects a phosphorylation event at the endogenous level and was a key reagent in a publication this year. 
 
Title NMDA receptor trafficking reagents 
Description We have developed novel tools, methodology and analysis methods for visualising/analysing NMDA receptor movements within axons and dendrites of cultured neurons. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact These tools are currently being used to investigate NMDA receptor motility within neurons, and how this is affected by candidate risk factors for major mental illness. Our first manuscript is in preparation for publication. 
 
Title PDE4B expression constructs 
Description PDE4B expression constructs modified for ease of protein expression detection. 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact Constructs are currently in use for various projects. 
 
Title expression constructs 
Description a large number of expression constructs designed to examine DISC1 and interactors at the level of protein binding, phosphorylation, clinically relevant mutations, genetic variants, localisation etc 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact We have been providing reagents to many laboratories (internationally) for a number of years. The materials are in current use by many laboratories for general protein biochemistry experiments. 
 
Title t(1;11) family IPS cells 
Description Several induced pluripotent stem cell lines from the t(1;11) family have been developed and subjected to quality control checks. A number of these have undergone neural conversion. 
Type Of Material Cell line 
Year Produced 2013 
Provided To Others? Yes  
Impact The IPSC lines and derivatives are still under investigation. They are widely recognised as a valuable tool for research into major mental illness and we have received/agreed to several requests for access to the lines or material derived from them. 
 
Description CSHL sequencing 
Organisation Cold Spring Harbor Laboratory (CSHL)
Country United States 
Sector Charity/Non Profit 
PI Contribution We provided information about promising candidate genes for genomic resequencing in patients with a diagnosis of mental illness.
Collaborator Contribution Our collaborators Richard McCombie and James Watson are providing genomic sequence information for DISC1 and a subset of DISC1 binding partners. A matched set of controls and cases diagnosed with major mental illness are being sequenced to identify putative causal mutations. Such mutations will be tested in a range of our biochemical assays.
Impact This collaboration has identitifed a further instance of a severe mutation in DISC1, previously identitifed in one case only. This mutation may thus be more prevalent than previously thought. A manuscript describing the first round of data has now been published: '708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits'. This collaboration is not multi-disciplinary.
Start Year 2007
 
Description Carragher lab 
Organisation University of Edinburgh
Department Institute of Genetics & Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We will provide lysates from human induced -pluripotent stem cell (IPSC)-derived neural precursor cells and a corresponding mouse model for analysis using reverse phase protein arrays to identify signalling pathway alterations. We are also currently contributing to optimisation of various automated systems for analysis of IPSC-derived cells and material.
Collaborator Contribution The Carragher lab is providing access to various automated systems and working with us to optimise their use for IPSC-derived material.
Impact A number of signaling pathways have been identified in neural precursor cells derived from translocation carriers. We are also developing a neural reverse-phase protein array panel for use with IPSC-derived cell sfrom patients with a variety of brain disorders.
Start Year 2014
 
Description CeGaT 
Organisation Center for Genomics and Transcriptomics (CEGAT)
Country Germany 
Sector Private 
PI Contribution Provision of RNA samples for RNAseq, bioinformatics analysis.
Collaborator Contribution RNAseq and bioinformatics analysis
Impact RNASeq analysis was carried out on two brain regions from a novel mouse model of major mental illness based on the t(1;11) translocation. This analysis identified a number of altered processes which are likely to affect brain function and which point to potential disease pathways in major mental illness. They include synaptic functions, intracellular trafficking, axon outgrowth and guidance, dendrite and spine development and many more.
Start Year 2016
 
Description Chandran lab 
Organisation University of Edinburgh
Department School of Molecular and Clinical Medicine Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution We have generated induced pluripotent stem cells from members of the t(1;11) family, and carried out all necessary quality control checks. We are growing and analysing resultant neural precursor cells and neurons, bringing our expertise in DISC1 biology and protein biochemistry to the project. This collaboration also involves psychiatrist Andrew McIntosh and is funded by the MRC (MR/J004367/1).
Collaborator Contribution Growth of skin fibroblasts, neural conversion of IPS cells, quality control and analysis of neural precursor cells and derived neurons.
Impact Induced pluripotent stem cells, neural precursors and neurons have been generated and are currently undergoing analysis. This collaboration is not multidisciplinary.
Start Year 2010
 
Description David Price 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom 
Sector Academic/University 
PI Contribution We are jointly supervising a PhD student who is investigating developmental effects of DISC1 expression. We have provided DISC1 expression constructs, investigated DISC1 antibodies for use in mouse, and shared our knowledge of DISC1 biology. We are now jointly supervising a second PhD student who is investigating brain anatomy, development and function in a new DISC1 mouse model.
Collaborator Contribution David Price provides his exeprtise in developmental biology and the associated methodologies.
Impact We have identified novel effects of DISC1 upon the developing brain, now published doi:10.1371/journal.pone.0156082. This collaboration is not multi-disciplinary.
Start Year 2009
 
Description Generation Scotland 
Organisation Generation Scotland
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Generation Scotland was conceived and established by David Porteous through successful funding applications led by him.
Collaborator Contribution Generation Scotland have provided samples for genotyping.
Impact Multiple studies involving Generation Scotland samples have now been published. This collaboration is not multidisciplinary.
Start Year 2006
 
Description Giles Hardingham lab 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing brain tissue and RNAseq data from the mouse model of the t(1;11) translocation for electrophysiology and general analysis.
Collaborator Contribution Electrophysiology and data analysis/interpretation.
Impact ongoing
Start Year 2016
 
Description Kaibuchi lab 
Organisation Nagoya University
Department Graduate School of Pharmaceutical Science
Country Japan 
Sector Academic/University 
PI Contribution We have carried out confirmatory validation of the knock-out status of a mouse model and specificity of a DISC1 antibody generated by the Kaibuchi lab. We have used these materials to validate additional antibodies and to demonstrate synaptic expression of endogenous DISC1. We provide this type of information to the Kaibuchi lab.
Collaborator Contribution Provision of antibody and material from knock-out mice.
Impact a study utilising knock out mouse brain lysates has been published: 'Disc1 variation leads to specific alterations in adult neurogenesis'. This collaboration is not multi-disciplinary.
Start Year 2011
 
Description Korth lab 
Organisation Heinrich Heine University Düsseldorf
Department Institute of Neuropathology
Country Germany 
Sector Academic/University 
PI Contribution We have provided t(1;11)-derived material for analysis and have attempted to validate a number of DISC1 antibodies. We have contributed to a successful European Union Framework 7 application.
Collaborator Contribution We have been provided with a number of antibodies for validation. The Korth lab is also attempting to generate monoclonal antibodies specific for aberrant DISC1 species that may be expressed by t(1;11) carriers.
Impact This collaboration has contributed to a successful European Union Framework 7 funding application. This collaboration is not multidisciplinary.
Start Year 2011
 
Description McIntosh 
Organisation University of Edinburgh
Department Division of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution We are working with Andrew McIntosh and Siddharthan Chandran to generate and analyse induced pluripotent stem cells and neurons from the t(1;11) family. This work is funded by the MRC (MR/J004367/1). We have produced induced pluripotent stem cells, carried out quality control checks and are currently growing/analysing derived neural precursor cells and neurons.
Collaborator Contribution Andrew McIntosh is a psychiatrist working with the t(1;11) family and has a general involvement in the entire iPS cell project. Siddharthan Chandran has generated neural precursor cells from the IPSC. We are now working closely with the Chandran lab to characterize the human cells and the corresponding mouse model on a variety of measures.
Impact iPS cells have been generated and more are on the way. neural precursor cells and derived neurons have been generated and these cells are currently undergoing a variety of analyses. This is a multidisciplinary collaboration involving psychiatry, cell biology, transcriptomics, proteomics and more.
Start Year 2010
 
Description Sanofi 
Organisation Sanofi
Department Aventis
Country France 
Sector Private 
PI Contribution We have analysed DISC1 expression in Sanofi-generated DISC1 mutant mice by quantitative RT-PCR. We have bred the mice to a pure background ready for full analysis. We are carrying out analysis of brain structure and development, effects upon DISC1 function, RNASeq etc and have identified a number of collaborators to assist with characterisation/analysis of the model.
Collaborator Contribution Provision of RNA samples from a range of tissues and developmental stages. provision of mutant mice that model the t(1;11) translocation.
Impact We have demonstrated, at the transcript and protein level, that these mice are a good model of the t(1;11) translocation. We have instigated collaborations with several labs to characterize the mice as thoroughly as possible. We have identified a number of changes due to the Disc1 mutation in these mice, many of which are likely to be relevant to psychiatric illness. A number of collaborative manuscripts are in preparation.
Start Year 2011
 
Description Smit lab 
Organisation Free University of Amsterdam
Country Netherlands 
Sector Academic/University 
PI Contribution Provision of a mouse model of major mental illness for proteomics research, provision of RNAseq data from the same model for comparison.
Collaborator Contribution Analysis of the effect of the translocation upon synaptic protein complexes
Impact A number of interesting alterations to synaptosomal protein expression have been identified. These match up well to the RNAseq data.
Start Year 2015
 
Description Sylics 
Organisation Sylics
Country Netherlands 
Sector Private 
PI Contribution We are providing a validated mouse model of mental illness and will share any data obtained on brain structure and protein biochemistry.
Collaborator Contribution The mouse model will be subjected to a comprehensive behavioural analysis
Impact None yet. This collaboration is multidisciplinary, involving mouse behaviour, neuroscience, cell biology and protein biochemistry.
Start Year 2014
 
Description Walkinshaw lab 
Organisation University of Edinburgh
Department Institute of Structural and Molecular Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have devised projects and provided all necessary materials to Malcolm Walkinshaw.
Collaborator Contribution We have been given access to the Edinburgh Protein Production Facility, other equipment necessary for biophysical characterisation of proteins, expert advice and training.
Impact This collaboration has so far resulted in two papers: 'The Mitosis and Neurodevelopment Proteins NDE1 and NDEL1 Form Dimers, Tetramers, and Polymers with a Folded Back Structure in Solution' and 'A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins'. This project is multidisciplinary involving protein biochemistry and structural biology.
Start Year 2009
 
Description Wyllie lab 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided DISC1 mutant mice for electrophysiology on brain slices. This work was funded by the MRC (G0902166). We will provide a variety of DISC1 and partners expression constructs for use in neuronal patch-clamp experiments.
Collaborator Contribution The Wyllie lab have carried out electrophysiology and have provided equipment, training and expertise for neuronal patch-clamping. They are now assisting with electrophysiology on the t(1;11) mouse model.
Impact The Wyllie lab have demonstrated that NMDA receptor function is grossly normal in the ENU mutant mice, however subtler deficits have not been investigated. This collaboration is multi-disciplinary, involving electrophysiology and cell biology/ protein biochemistry.
Start Year 2010
 
Description drug screening collaboration 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution My team has provided expertise and data derived from genuine schizophrenia models that strongly highlight a pathway of interest for drug discovery in schizophrenia.
Collaborator Contribution Edinburgh Innovations bring their expertise in industrial partners and commercialisation. Neil Carragher brings his expertise in high throughput drug discovery. e-therapeutics bring their expertise in bespoke compound library building through network analysis.
Impact So far this collaboration has led to a (currently underway) funding application for MRC Confidence in Concept funding to deliver the first phase of screening work.
Start Year 2017
 
Description drug screening collaboration 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution My team has provided expertise and data derived from genuine schizophrenia models that strongly highlight a pathway of interest for drug discovery in schizophrenia.
Collaborator Contribution Edinburgh Innovations bring their expertise in industrial partners and commercialisation. Neil Carragher brings his expertise in high throughput drug discovery. e-therapeutics bring their expertise in bespoke compound library building through network analysis.
Impact So far this collaboration has led to a (currently underway) funding application for MRC Confidence in Concept funding to deliver the first phase of screening work.
Start Year 2017
 
Description Annual lecture to Bipolar Fellowship 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Annual lecture

Feedback and daalogue by email
Year(s) Of Engagement Activity 2007
 
Description CWMT Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Invited keynote research summary for Charle Whaller Memorial Trust Newsletter

Feedback from readers
Year(s) Of Engagement Activity 2008
 
Description Edinburgh City Council 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Circa 150 people attending the meeting which comprised a formal presentation followed by a Q&A session.

Higher level of awareness of the project in lay and public sectir groups.
Year(s) Of Engagement Activity 2006
 
Description Edinburgh Science Festival 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact School children were interested, participated and asked questions.

The continuing success of the Edinburgh Science Festival demonstrates its impact. Children were asked to rate their experience and did so very positively.
Year(s) Of Engagement Activity 2013
 
Description Edinburgh Science Festival presentation 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact We prepared a stall designed to interest school children in the subject of genetics and to introduce the idea that many of our characteristics are inherited. The children showed a lot of interest in this idea. We also included some information on mental illness and genetics for parents, designed to demonstrate how prevalent mental illness is, illustrated by a list of famous people with a diagnosis of schizophrenia or depression. This part of our stall had a big impact. We contribute every year to the Science Festival and other University/MRC workshops aimed at school children.

The excellent annual attendance at the festival demonstrates its impact.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Gengage talk to school biology students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 120 pupils attended talk on genetics and ethics plus Q & A.

Strong feedback from teachers and pupils attending.
Year(s) Of Engagement Activity 2010
 
Description ICCD Conversations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk to ICCD supporters at networking meeting.

Invited back to talk at further meeting in New York (2009) and Glasgow (2009). Links to potential co-sponsors of mental health research.
Year(s) Of Engagement Activity 2008
 
Description Keynote talk to Federation of Scottish Biology Teachers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Schools
Results and Impact Over 100 Scottish biology teachers attended.

Follow up from teachers and direct contacts with a view to developing new materials for Scottish curriculum teaching.
Year(s) Of Engagement Activity 2008
 
Description Royal Society of Edinburgh, Bruce Preller Lectureship 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Circa 150 people attending the meeting which comprised a formal presentation followed by a Q&A session.

Follow up by attendees for further information
Year(s) Of Engagement Activity 2008
 
Description Science Insights programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact A group of students learned about our IPS cell project, carried out PCR to determine translocation carrier status and examined neuronal cultures by fluorescence microscopy.

none yet
Year(s) Of Engagement Activity 2014
URL http://www.scienceinsights.ed.ac.uk
 
Description University of Edinburgh department of Neuroscience Christmas Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A lay lecture was given by DP, followed by poster presentations at a reception. The lecture audience was free to attend the posters and discuss the work presented.
Year(s) Of Engagement Activity 2015