The supervisors of the 5 research teams introduce themselves and their group.
1.1 VU University Medical Center Amsterdam (VUmc)
Department of Functional Genomics, Amsterdam, the Netherlands
Prof. Peter Heutink
The increasing prevalence for neurodegenerative disease in our aging population poses a growing problem for healthcare. It is therefore not surprising that the development of treatments for these chronic and irreversible brain disorders is rated as high priority in the recent WHO report on ‘Priority Medicines’. In Alzheimer’s and Parkinson’s disease, years of slowly progressing neurodegeneration, set the stage for devastating clinical phases. Most neurodegenerative diseases have in common that neurons and synaptic contacts atrophy, gradually loose their function and are then lost. With this in mind, future treatments have to be aimed at boosting the survival and repair potential of affected neurons during the very early clinical phases of these diseases. In the vast majority of patients with dementia, single mutations are not sufficient to explain the disease pathology, but a combination of genetic mutations interacting with environmental factors increase the risk for developing disease. Therefore the key objective is to uncover the complex etiology of pathological brain dysfunction, for dementia and milder age related cognitive decline, by focusing on genetic mechanisms. Recently, we identified several new genetic risk factors that we will study in High-Throughput/High-Content cellular screens. Due to the complexity of the genetic risk we will focus on using patient derived iPS cells.
1.2 Riken Omics Science Center
Functional Genomics Technology Team, Yokohama city, Japan
Dr. Piero Carninci
Our center focus is to develop and apply “omics” technologies to a various range of biological phenomena including neurodegenerative disorders. We have been contributing to the discovery of classes of large non-coding RNAs and to the annotation of the mouse transcriptome in the early Functional Annotation of the Mammalian (FANTOM) projects. Next, we have developed the cap-analysis gene expression (CAGE) technology, which allows mapping promoters and measuring their expression simultaneously. The technology was further adapted to a small amount and renamed as nanoCAGE. For the Braintrain project, we are broadly applying CAGE and nanoCAGE to samples of neurobiological interest, including human and mouse brain regions, mouse GFP labeled neurons and RNA extracted from the whole blood of patients. Further analysis provides information regarding all the mRNA isoforms and of large non-coding RN that are expressed from different promoter in nervous tissue and isolated neurons and measure the expression of each of these isoforms. Further analysis allows also prediction of the transcriptional regulatory networks.
1.3a Scuola Internazionale Superiore di Studi Avanzati (SISSA)
Neurobiology sector/Labority of Neurogenomics, Trieste, Italy
Dr. Stefano Gustincich
Stefano Gustincich obtained his PhD at SISSA, Trieste, Italy, working with Prof. Claudio Schneider on molecular cloning of genes involved in the negative control of cell proliferation. He was awarded a Long-term EMBO fellowship to work as a post-doctoral fellow in the laboratory directed by Prof. Elio Raviola at the department of Neurobiology at Harvard Medical School, Boston, USA. He developed a transgenic model to study the function of dopaminergic neurons of the retina, a rare neuronal cell type involved in the control of light adaptation. In 1998, he became Instructor in Neurobiology at Harvard Medical School where he developed techniques to study gene expression at single cell level, identifying genes expressed in single dopaminergic neurons. He has been awarded the Harvard-Armenise career development award to join the Laboratory of Molecular Neurobiology at SISSA as a principal investigator. Since 2005 he is Associate professor in Physiology at SISSA where he teaches courses in “Molecular Biology of the Cell – Advanced” and “Functional Genomics’
1.3b Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)
Our laboratory has always been interested in studying the molecular mechanisms underlying pathogenicity in neurodegenerative disorders including frontotemporal lobar degeneration (FTDL) and Parkinson’s disease. In this context we have pursued genetic studies toward finding of genes responsible for the more rare forms of the diseases where the disease is inherited according to Mendel’s law and studies aiming to highlight the genetic contribution to the etiological process and pathogenesis of the more common and complex forms of the neurodegenerative disorders. The ultimate goal of our research is to create cellular models that truly mimic disease and that can be used to find ideal targets for future therapy.
To achieve such goal we however need to understand how pathogenic mutations and genetic variants disease associated can influence genes networks with which interact in a direct and indirect manner. We decided therefore to take a genome wide transcriptomic approach using CAGE analysis and RNAseq on RNA from FTDL patients and controls brains to reveal and dissect gene networks and pathways perturbed in the different pathological subtypes of FTDL focusing particularly on functional characterization of non coding RNAs.
2.1 VU University Amsterdam (VU)
Department of Molecular and Cellular Neuroscience, Amsterdam, the Netherlands
Prof. Guus Smit
We are interested in the organization of synaptic proteins into multi-protein complexes and the way synaptic proteins and complexes interact. In BrainTrain our focus is on proteins that interact with the glutamate receptor and that may be of importance for function of the receptor. This is the trafficking into the membrane, the retrieval of receptors, or the modulation of biophysical properties. For studying the synaptic interactome we will use immunoprecipitation and mass spectrometric analysis for identification of proteins. In collaboration with other partners we will investigate the interaction kinetics of the proteins involved.
2.2 Leibniz-Institut für Neurobiologie (IfN)
Institute of Anatomy and Cell biology / Center for Interdisciplinary Neuroscience (IZN), Magdeburg, Germany
Prof. Eckhardt Gundelfinger
The group will study plasticity mechanisms of the synapse-associated extracellular matrix (ECM) in health and disease. The ECM is a meshwork of highly cross-linked proteoglycans and glycoproteins covering the surface of most neurons. It undergoes massive changes during nervous system development. The adult ECM that is formed late during development is thought to define plasticity properties of the adult brain. Research will include the profiling of components of the ECM under various physiological and pathophysiological conditions as well as the analysis of mechanisms of activity-dependent remodeling of the perisynaptic ECM. In particular, the role of ECM-modifying and -degrading enzymes, such as hyaluronidases and matrix metalloproteinases, in plasticity processes and in pathology of the adult central nervous system will be studied. This partner will provide know-how in glycobiology and biochemistry of the ECM as well as imaging of local cell surface processes including single molecule tracking and two-color STED microscopy.
2.3 Beatica AB
www.beactica.com, Uppsala, Sweden
Prof. Helena Danielson
Beactica is using SPR biosensor technology for identification and optimization of leads towards various diseases, including neurological disorders. In this project we will be dedicated to the characterization of interactions between different synaptic proteins. The aim is to both define the proteins participating in the synaptic interactome and to identify factors that regulate or influence the identified interactions. The work will primarily involve SPR biosensor analysis, complemented by other experimental techniques for interaction and computational methods for modelling interactions. The focus will be on interactions with the AMPA receptor under different physiological conditions (e.g. Ca2+ dependence). We will be collaborating closely with groups producing these challenging membrane bound proteins and other groups that have complementary experimental expertise.
3.1 VU University Medical Center Amsterdam (VUmc)
Department of Functional Genomics, Amsterdam, the Netherlands
Dr. Heidi de Wit (coördinator)
We are interested in the molecular and cellular mechanisms of neurotransmission as well as secretory vesicle trafficking in diseased synapses of various mouse models for brain diseases (e.g., fragile X mental retardation). Recently, we identified novel presynaptic mechanisms involved in synaptic plasticity and in docking of secretory vesicles at the target membrane. In BrainTrain our focus is to elucidate how genes linked to synaptopathies cause alterations in the molecular architecture of the synaptic machinery. For this we will use high-resolution imaging methods like immuno-electron microscopy (EM) together with innovative cryo-EM methods (3D) and correlate this with observations in living cells (i.e. TIRF). In collaboration with other partners we will investigate consequences of mutant synaptic proteins on synapse physiology and organization of release machineries.
De Wit will coordinate BrainTrain, assisted by an experienced EU manager from the SME (Synaptologics B.V.) for management, networking and training activities.
3.2 University College London (UCL)
Department of Physiology, London, United Kingdom
Prof. Angus Silver
The main aim of my lab is to develop a mechanistic understanding of information processing in the brain that links the molecular, synaptic, neuronal and network levels. This requires a multidisciplinary approach that combines the most powerful experimental and theoretical methods available. To achieve this we both develop and apply new optical methods for measuring rapid signalling in 3D and new software tools for data acquisition, analysis and modelling. Application of these new experimental and theoretical approaches to the cerebellum and sensory cortex allows us to link neuronal mechanisms to information processing, thereby bridging different levels of description of brain function.
3.3 Universitätsklinikum Heidelberg (UKL-HD)
The group studies the structure and function of mammalian central synapses, mostly focusing on presynaptic nerve terminals. We aim at understanding how defined presynaptic proteins contribute to the properties of synaptic transmission, and how these properties relate to network function and behavior. The group uses a variety of state-of-the-art molecular perturbation technologies including viral gene transfer and stereotaxic delivery. We use model synapses such as the Calyx of Held or the corticothalamic Rosebud synapse for selective perturbations and the assessment of structural, functional and behavioral consequences.
4.1 Sylics (SYL)
The project partner and Early Stage Researcher will work within Synaptologics (WP 4) to characterise the spatial and temporal patterns of synaptic activity and plasticity mechanisms underlying development of cortical and hippocampal neuronal circuits. In inherited neurodevelopmental disorders of autism and mental retardation, the genetic effects on the development and maturation of brain activity are not known. We will use electrophysiology and imaging techniques to establish whether synaptic network function is altered during early brain development in genetic mouse models of autism and mental retardation.
4.2 Katholieke Universiteit Leuven (KUL)
Department of Molecular and Developmental Genetics, Leuven, Belgium
Prof. Claudia Bagni
4.3 Institut Pasteur (IP)
Centre National de la Recherche Scientifique (CNRS) / Laboratory of Integrative Neurobiology of Cholinergic Systems, Paris, France
Dr. Uwe Maskos
Our laboratory focuses on a couple of major issues in public health. 100 million people are expected to die this century from the consequences of nicotine addiction, yet nicotine is also known to enhance cognitive performance. There is clear cut epidemiological evidence in the medical literature, confirmed by meta-analyses, that smoking protects against Parkinson’s Disease (PD) and also Alzheimer’s Disease (AD). Additionally, nicotinic acetylcholine receptors (nAChRs) are down-regulated in serious human psychiatric conditions like autism. Hence, the identification of the molecular mechanisms and circuits involved in nicotine reinforcement, nicotine mediated neuroprotection, and cognition is urgent and requires the development of novel tools that allow genetic and molecular manipulation in vivo, in experimental animals.
5.2 Sylics (SYL)
This group, as part of Synaptologics and will focus on advanced behavioral and autonomic phenotyping of mouse models of affective disorders together. Besides the use of a spectrum of behavior tests, this line of research is strengthened by the development of a fully automated behavior system to investigate aspects of fear learning for prolonged time periods (days) under home cage conditions without human interference. Automated home cage-based phenotyping is achieved in close collaboration with Christian Gutzen, Biobserve, and is used to characterize mouse models of depression partly from the group of Per Svenningsson, KI. Autonomic phenotyping includes the assessment of nonlinear heart rate dynamics that is determined by brain function and has translational value from mouse to man.
5.2 Karolinska Institutet
Department of Physiology and Pharmacology, Stockholm, Sweden
The group will contribute with its expertise in study of intracellular signaling in vivo and in vitro. The work will include in vivo studies of actions via GPCRs, adaptor proteins and protein phosphorylation pathways in response to pharmacological and behavioural stimulation in wild type and mutant mice. An emphasis will be put on serotonin-mediated modulation of glutamatergic transmission. The group will closely interact with other partners and provide data for modeling.
5.3 BiObserve GmbH (BiObserve)
BiObserve, Bonn, Germany
Our task is to deliver the software to run and analyze the behavioral long-term experiments in the lab of Oliver Stiedl. Besides the existing video-tracking system that is used to monitor the animals behavior 24 hours continuously for several days, we develop additional software modules to control the experiment in a flexible way based on several parameters (event triggered latencies, behavior of the animal, time controlled) and to synchronize and integrate the data acquisition of various independent measures.
The main focus is to develop new non-linear algorithms to analyze the behavior of the animal over a period of several days, which has never been done before in such a detailed way.