In-Sens Partner description
IESR1 Multimer-dependent interactions and functions within the DISC1 pathway
My laboratory is interested in how different conformations of a protein or different multimerization states of a protein are used to modulate biological functions in health and disease, with a focus on the brain. In particular, we have been focussing on analyzing protein pathology in chronic mental illnesses (CMI) like schizophrenia or the recurrent affective disorders. We have been employing proteomic, epitope discovery and candidate protein techniques to identify differences in proteostasis in human mental illness brains, and, ultimately, to identify candidate protein pathways aberrant in behavioural disorders. For the disrupted-in-schizophrenia 1 (DISC1) protein we have paradigmatically demonstrated its existence in an insoluble form in the post mortem brain in a subgroup of patients with various clinical phenotypes of CMI. We have been modelling these DISC1 multimers by creating a transgenic rat model and done functional investigations in this model demonstrating a behavioural phenotype. In research that is about to be published, we could demonstrate there is a continuum of DISC1 multimers that actually is functional in regulating dopamine homeostasis. Thus, DISC1-dependent disorders may constitute a biologically defined subgroup of mental illnesses, or “DISC1opathies”, and DISc1 multimerization may define a novel pharmacological target. We are currently further investigating the role of other protein multimers in chronic multimers in regulating behavioural functions.
IESR2 Exploring the DISC1-VGF connection in chronic mental illnesses
My laboratory is focused on the study of the role of protein malfunction in neurodegenerative diseases. In particular, we are very interested, although not limited to, malfunction as a consequence of misfolding and aggregation. Several years ago, we started a collaboration with Carsten Korth´s group (IESR1 and project coordinator) aimed at exploring a possible role of protein aggregation in the pathology of chronic mental illnesses (CMIs). The exciting underlying hypothesis is that CMIs might share pathological molecular mechanisms with protein misfolding-based neurodegenerative diseases such as Alzheimer´s or prion diseases. Throughout this collaboration, our group participated in studies that showed that DISC1, a protein that is truncated in a Scottish family with a high prevalence of CMI, forms insoluble aggregates in a subset of cases of mental disease. Following these studies, we have recently discovered that DISC1 regulates the expression of VGF, a neuropeptide precursor with potent antidepressant and neurotrophic properties (manuscript submitted). Therefore, we hypothesize that some of the roles of DISC1 deficits in mental disease might be mediated by reduced expression of VGF. In this context, our group´s participation in INSENS will aim at investigating the molecular biology of this new member of the extended DISC1 pathway using a variety of molecular, cellular and animal tools, in close collaboration with the other groups.
IESR3 Structural and ultrastructural investigations of DISC1 aggregates
IESR4 Mitochondrial effects of abnormal DISC1 expression
Centre for Genomic and Experimental Medicine (CGEM)
MRC Institute of Genetic and Molecular Medicine (IGMM)
The University of Edinburgh
My research centres around understanding the molecular mechanisms by which inheritance of a balanced t(1;11) chromosomal translocation substantially increases risk of developing schizophrenia, bipolar disorder or recurrent major depression in a large Scottish family. This translocation directly disrupts the DISC1 gene, an event that likely contributes to the disease mechanism. We are researching the function of DISC1 to identify potential pathways leading to increased risk of psychiatric illness in translocation carriers. To aid with this research several translocation carriers and their relatives have generously donated tissue, which has been reprogrammed to produce induced pluripotent stem cells which will, in turn, be differentiated to produce neurons. Focussing particularly upon analyses of mitochondrial deficits and intracellular trafficking, we will use this unique new resource and a number of additional model systems, to investigate normal DISC1 function, and DISC1 dysfunction in psychiatric illness.
IESR5 The extended DISC1 interactome
IESR6 Synaptic function analysis in cellular models of SCZ
My research focus is on synaptic dysfunction in psychiatric and neurodegenerative disease. Over the years it has become clear that disturbances in synaptic function are causally related to circuitry and systems failure in the brain. Underlying disturbances in protein interactions are likely causative. For that reason we have developed methods to identify protein interactions around proteins that may form important signalling nodes. In INSENS, identifying the extended interactome of DISC1 may therefore be of interest to understand its (synaptic) function, both in neurons as well as in patient derived iPSCs. In addition, functional analysis of proteins of the extended interactome may aid in shedding light of their contribution to function and maintenance of the synapse. In particular, specifically developed confocal high content automated cellular assays may assist in deciphering function of proteins at a larger scale.
IESR7 In vivo cholinergic/dopaminergic neurotransmitter interactions with DISC1
The Center for Behavioral Neurosciences at the University of Düsseldorf (Dir. Joseph P. Huston) has long served as a prominent facility for the study of the behavioural neurosciences, with emphasis on the relationships between behavioural and biological manifestations of degenerative diseases, psychopathologies and aging. We are particularly interested in the role of the brain’s neurotransmitter systems in the mediation of fundamental behavioural processes, in particular the mechanisms that underlie cognitive and motivational functions. The team is composed of visiting scientists from around the world and of graduate students pursuing their MS and PhD degrees. In our facilities we have a wide range of behavioural methods available to gauge processes in rats and mice related to learning, memory, motivated behaviour, emotional behaviours, sensorimotor and perceptual functions. Animal models for neurological and psychiatric disorders are available for Parkinson’s disease, Alzheimer’s disease, age-related cognitive deficits, anxiety disorders, addictive behaviour and schizophrenia. At the Primate Center of the University of Brasilia we have access to Cebus and Callitrix monkeys for behavioural-pharmacological studies. Our neurochemical labs are equipped with techniques that include the in vivo microdialysis of neurotransmitters in specific brain sites in freely-moving and behaving rats, used in association with the high performance liquid chromatography for the analysis of several neurotransmitters.
IESR8 In vivo electrophysiology in DISC1 transgenic and mutant animals
Prof. Jozsef Csicsvari
Institute of Science and Technology Austria
The research in my laboratory aims at revealing the behavioural role of oscillatory activity in the hippocampus, and understanding the physiological mechanisms behind these oscillations. We investigate the mnemonic role of the hippocampus both in terms of defining the part played by network oscillations and characterising the activity and interactions of cell assemblies during different stages of memory processing with a special focus on the role of sleep in memory consolidation. We use wide variety of techniques including wide variety of behavioural learning paradigms, multichannel electrophysiological recordings, complex computer data analysis methods and pharmacological and molecular genetics, including optogenetic approaches. Within INSENS we will investigate alterations in network oscillations in transgenic models of schizophrenia involving the extended DISC1 pathway and test whether these alterations can explain behavioural alterations.
IESR9 Behavioural signature of the extended DISC1 pathway, and the role of PV interneurons therein
At Sylics, we aim to contribute to a better understanding and treatment of neurological and psychiatric diseases, such as schizophrenia, by systematically studying the behaviour of mouse models of these diseases. We focus on understanding mechanisms contributing to cognitive performance in tests of learning and memory and executive function. Our strength is the development of novel behavioural tests in an automated home cage environment. We know that testing of mice in their familiar environment improves animal welfare and reduces confounding human-animal interactions, providing increased sensitivity to detect disease phenotypes and treatment effects. The systematic, automated nature of home-cage testing allows comparison of mouse models to better understand disease phenotypes and efficient screening for new treatment options. To functionally test hypothesis on underlying mechanisms, we use a range of intervention techniques, such as brain-region and time restricted expression of genes, and stimulation of particular cell circuitry. In summary, in collaboration with academic and commercial partners around the world, we develop and validate novel behavioural tests, create innovative mouse models of human diseases, and screen for new options to treat these diseases.
IER10 DISC1 and cerebellar-cortical network function
Dr Elin Åberg and Nick Brandon
My career has focused on developing novel approaches for the treatment of principally mental disorders within large biopharmaceutical companies. My research lab has spent the last 12 years working on DISC1 and amongst other achievments established the DISC1 interactome as a platform to dissect out DISC1 function and interrogated a role for DISC1 at the synapse. In addition we have heavily focussed on the role of phosphodiesterases which again dissects with DISC1 at the level of PDE4. I currently have a keen interest in the application of cutting edge human genetics, iPS/stem cells and in vivo electrophysiology for the next wave of drug discovery. Within this partnership I will be collaborating with Dr Elin Aberg to look at the role of the cerebellum in a DISC1 rat model and analyze connectivity with other brain regions.
The postdoc recruited into this project will work in a vibrant and creative environment at the AstraZeneca Translational Science Centre located at Karolinska Institutet, Sweden. This center is focused on discovering and delivering innovative biomarkers for clinical use and consists of three main functions; Neurophysiology, Biochemistry and PET. The core platform in the Neurophysiology group is the EEG set-up used as a central functional translational biomarker. This is a rodent telemetric EEG system, where brain activity, body temperature and locomotor activity can be followed in a homecage environment over a long period of time. This gives us the opportunity to follow disease progression and pharmacodynamic effects. We will in this project explore and electrophysiologically profile the relationship between cerebellar output and the prefrontal cortex in vivo in a novel DISC1 [“Disrupted in Schizophrenia”] transgenic rat as compared to wildtypes at different ages, and will examine the expression pattern of synaptic proteins in the cerebellum. These experiments are important to further define the previously underestimated role of the cerebellum in mental disorders.
IESR11 DISC1 and Underlying Gene Networks in Schizophrenia
We are interested in studying psychiatric disorders, such as schizophrenia, through the analysis of the genetic mechanisms that undoubtedly underlie them. We use next generation sequencing to identify functional variation within genomic regions that have been targeted based on prior evidence for involvement in schizophrenia in the Finnish population, principally the DISC1 locus. It is expected that any functional variation identified will be “neither necessary, nor sufficient” to cause schizophrenia. Therefore, such variants will be followed-up in order to address both those issues. In order to understand the wider genetic aetiology, identified functional variants are fed back, through conditional analysis, into the genome-wide data. The aim is that this reduces the genetic heterogeneity in the two conditioned sub-samples, thus aiding the discovery of novel genomic regions that are either independent of, masked by, or dependent on the original observation. Further, since any functional mutations identified will increase risk to, but not cause, a psychiatric diagnosis, it is important that we study them with regard to alternative traits. This would enable us to translate these findings, improving our understanding of how the brain works. We have access to neuropsychological, biological and treatment related measures, which we use to start the unravelling of the true function of these genetic variants.
IESR12 Affinity Proteomics for discovery of new potential biomarkers
The main research focus is within development and utilization of various protein microarray technologies for proteomic profiling and biomarker discovery. This is mainly enabled by utilization of the massive antigen and antibody production pipeline within the Human Protein Atlas as well as whole proteome ultra-high-density peptide microarray.
Broad analysis of autoimmunity repertoires is performed with serum, plasma and CSF samples, based on antigen and peptide based profiling within various neurodegenerative diseases as well as psychiatric disorders utilizing thousands of targets. Furthermore, large set of samples are also profiled with massive numbers of antibodies on highly multi-parallel suspension bead arrays which utilizes magnetic color-coded beads functionalized with antibodies to generate protein profiles from labelled samples for biomarker discovery.
IESR13 Mechanisms underlying the dynamic control of gene expression of DISC1 pathway genes
Prof. Peter Falkai and Prof. Dr. Andrea Schmitt
Prof. Dr. Moritz Rossner
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University (LMU) Munich
We are working in the field of neurobiological schizophrenia research. Using animal models such as the TCF4 overexpressing mouse we are investigating gene-environment interactions, schizophrenia-related behaviour, disease-related pathways and morphological alterations. We are equipped with device for Next Generation Sequencing, a mouse behaviour unit, Cell Culture, and Laboratory for DNA analysis. For proteomic investigations we have a close collaboration to the Max-Planck Institute in Munich and for stereology analysis to the Institute of Anatomy Munich, Prof. Christoph Schmitz. In IN-SENS we aim at investigating the circadian expression of members of the extended DISC1 network in EEG-staged PBMCs from control subjects and antipsychotic-free schizophrenia patients as well as during follow up in remission on stable atypical antipsychotic medication. We will also analyse dynamic gene expression changes of members of the extended DISC1 network in mouse models of schizophrenia risk genes and effects of altered sleep-wake behaviour on cortical and hippocampal regions at different stages of alertness, and use phospho-proteomics to identify surrogate markers in the dynamics of DISC1 associated signalling pathways in forebrain regions.
The Department of Psychiatry, LMU Munich cares for 2.300 inpatients (20% schizophrenia patients) and has 22.000 outpatient contacts per year. We are conducting a series of clinical studies including psychopathological and neuropsychological assessments and MRI investigations. One of our aims is to develop innovative treatment strategies for schizophrenia based on molecular insights and pathophysiology of the disorder.
IESR14 DISC1 and dopaminergic function
Psychiatric Imaging Group, Clinical Sciences Centre-Imperial College and Institute of Psychiatry-King’s College, London, UK
Schizophrenia and other psychotic disorders are amongst the leading causes of global health burden. The Psychiatric Imaging Group’s research focuses on understanding the causes of psychotic disorders to develop new, improved treatment. The Group uses functional imaging including PET and MR techniques in patient and preclinical studies.
Current work in the Group focuses on:
- Understanding the brain changes that lead to the development of psychotic disorders, using multi-modal imaging with PET and fMRI
- Examining the influence of genetic variants linked to schizophrenia on brain function
- Determining why some patients respond to treatments and others don’t
In the last four years, ISI Thompson has identified 12 of the Group’s papers in the top 1% by citations in psychiatry and Faculty 1000 have identified nine papers as outstanding. In both 2009 and 2010 Science Watch identified the Group’s papers as amongst the top six in psychiatry by citations for the year. In addition Group members have received a number of awards, including the European Psychiatric Association Prize for Biological Psychiatry; European College of Neuropsychopharmacology Awards, and British Association of Psychopharmacology Wyeth prize.
- Medical / Clinical Science
- Psychiatry & Psychology
- Molecular Biology
- Imaging sciences
IER15 Identification of neuronal networks associated with schizophrenia clinical phenotypes by target exome sequencing analysis
Neuroscience is a major focus of research and development at Roche. We focus on three disease areas: psychiatric, neurodegenerative and neurodevelopmental disorders. One of the key areas of focus in psychiatry is schizophrenia for which we are investigating novel therapeutic approaches targeting negative symptoms and cognition improvement (most existing treatments target only positive symptoms).
The objective of the current project is the identification of genetic variations in inter- and intra-cellular signaling pathway that may help separate schizophrenia into different biological subtypes and drive patient stratification approaches in the clinics. The strategy is based on next-generation sequencing analysis of candidate pathways/genes in disease collections. An established bioinformatic and statistical analysis pipeline that includes variant analysis (annotation and identification of deleterious variants) and pathway-based aggregated analysis are used to test for variant enrichment in clinical subtypes.
At Roche, we use large-scale genomics analysis facilities and our expertise in biomarkers and personalised medicine to advance the understanding of the underlying biology of nervous system diseases.