Download Acronym + project logo: EUROSPIN Title - Max-Planck

Acronym + project logo: EUROSPIN
Title:
European Consortium on Synaptic Protein Networks
in Neurological and Psychiatric Diseases
Contract number:
HEALTH-F2-2009-241498
EC contribution:
11,952,691 €
Duration:
48 months
Starting date:
2010-01-01
Instrument:
Large collaborative project
Project web-site:
http://www.eurospin.mpg.de
Key words:
synaptopathies, systems biology, chemical biology, synaptic dysfunction, neuronal
networks, behaviour
Summary
Signalling at nerve cell synapses - a key determinant of all aspects of brain function - depends on hundreds of
synaptic proteins and their interactions. Numerous recent studies showed that a wide range of neurological and
psychiatric diseases are “synaptopathies” whose onset and progression are due to mutations of synaptic proteins
and subsequent synaptic dysfunctions. EUROSPIN will pursue a multilevel systems biology approach to determine mechanistic relationships between mutations of synaptic proteins and neurological and psychiatric diseases,
and to develop new diagnostic tools and therapies. Our concept is based on the current knowledge of disease
genes, which we will continuously extend with new human genetic data and complement with large-scale
screens of mutant mice in order to identify and characterize disease-relevant mutations in synaptic proteins and
corresponding mouse models. Proteomic tools will be used to analyse the protein components of synapses. Protein interaction networks of synaptic disease gene products will be mapped systematically. In parallel, smart libraries will be employed to develop small molecules for perturbing the functions and interactions of disease gene
products. Functional models of disease-relevant protein networks will be generated and used to formulate hypotheses as to how specific mutations might affect synaptic physiology and network function, and thus cause
disease. These hypotheses will initially be tested by novel physiological and imaging methods. Well-validated
disease gene products, the consequences of their dysfunction in disease, and therapeutic modifications of their
dysfunction will then be studied in mouse models in vivo, applying novel electrophysiological, imaging, and behavioural techniques. The combined information obtained in the EUROSPIN program will be used for the development of new diagnostic tools and therapeutic interventions that can be tested in patients.
Background
Synapses are fundamental brain structures that mediate information transfer between nerve cells. Signal transmission and information processing at synapses control all body functions and all aspects of cognition, including
attention, perception, learning, decision making, as well as mood and affect. Epidemiological, genetic, proteomics, and functional studies over the last decade have shown that synaptic dysfunction is central to the aetiology and progression of a wide range of neurological and psychiatric disorders, including neurodegenerative diseases, psychotic disorders such as schizophrenia, autism and affective disorders such as depression, which we
therefore collectively regard as synaptopathies. These diseases account for the majority of brain diseases, affecting roughly one third of the population during their life, and financially account for the largest single healthcare
burden in the European union member states. Accurate diagnosis and pharmacological intervention are significantly limited due to the severe lack of understanding of the molecular pathways that underpin normal and disease states. Although recognising that many psychiatric and neurological disorders are synaptopathies, functional
follow-up studies have been very rare and therapeutic approaches based on the synaptopathy model are basically
non-existent. This is due to the fact that the synaptopathy model poses a complex combination of conceptual or
methodological key-challenges. The central objective of the EUROSPIN consortium is therefore to systematically tackle these challenges with the ultimate aim of developing novel therapies for synaptopathies.
Aim: Facing the key challenges of the synaptopathy model and developing novel therapies
Synapses are sub-compartments of neurons with up to 2000 proteins that are organised into complexes and molecular networks. Based on single-gene mutation studies in mutant mice it is clear that synaptic properties require
the function of dozens to hundreds of genes. The benefit of the knowledge that a given protein may be involved
in a disease is therefore limited unless its interaction partners and molecular mode of action are known. The origins of synaptopathy disorders appear to be dysfunctions of the synaptic protein network rather than the dysfunction of an individual protein. Therefore we want to gain detailed knowledge of the synaptic protein network by
using a combination of single-gene/protein and multi-gene/protein approaches. In this regard, we will
•
analyse the synaptic proteome and interactome and provide a database,
•
model synaptic protein sub-networks of disease relevance, and
•
generate new mouse models that express tagged target proteins of disease-relevant protein complexes.
Our strategy is to first analyse 13 key gene products, identified from human genetic studies, that form hubs of
large synaptic protein networks whose mutations cause schizophrenia, autism, depression, ADHD, epilepsy,
mental retardation, Huntingtons disease, Tourette syndrome and Alzheimer's disease. The Eurospin partners
have in hand 176 mouse lines carrying mutations in synapse proteins that can be exploited in course of the project.
We will also focus on the physiological parameters that enable synaptic transmission. These cannot be studied
simultaneously since their analysis requires dedicated preparations, methods, and differentiated technologies. We
will study disease relevant mouse mutants and gene products at several levels of complexity, including
•
high throughput analyses of synaptic function and plasticity by multielectrode array recordings,
•
RNAi studies on disease gene products, and
•
imaging and electrophysiological studies on the trafficking and function of disease gene products.
Genetic alterations of synaptic proteins contribute significantly to the aetiology of most brain diseases. Our
initial set of 13 target genes will be extended by new candidate genes, identified by collaborating with human
clinical geneticists that give us direct access to new findings. Combining this information flow with proteomic
and transcriptomic discoveries will lead to the selection and development of promising new genetic mouse models.
Behaviour and disease symptoms can only insufficiently be explained by genetic, molecular, or synaptic dysfunction alone because neurons are usually operating in highly complex and extremely adaptive networks. We
will therefore also analyse dysfunctions at the level of neuronal circuits in vitro and in the intact brain by taking
advantage of
•
electrophysiological recordings from single neurons complemented by imaging technologies,
•
modelling normal network function and its perturbation using neuroinformatics, and
•
studying neural networks using primary neurons on multielectrode arrays, combined with RNAi.
By combining these methodological approaches, we will be able to decipher the complexity of psychiatric and
neurological synaptopathies and to develop tools for restoring normal function.
Mutant mice "carrying synaptopathy genes" must exhibit phenotypic characteristics that are related to symptoms in patients. We will define disease-relevant behavioural paradigms, including automated behavioural
screening, that can be used to assess the potential of drug therapies or gene therapy approaches. These studies
will create the necessary basis for subsequent attempts to restore synaptic dysfunction and reverting the behavioural symptoms of a given synaptopathy in mouse models.
Expected results
By focussing our research on more than 13 selected key model genes and well defined mouse models for common synaptopathies we will enter the "small molecules" track to therapy. We will develop small molecules,
starting from natural component libraries, and test modified variants in specific assays in order to determine
whether they are suitable for restoring normal synaptic network function. Compounds identified will be tested
within the consortium at all levels of analytical complexity, thus allowing for a systematic assessment of their
efficacy and translational potential. Our combined results will directly contribute to an increased understanding
of brain function, particularly at the synapse level.
EUROSPIN will dissect out detailed information on many of the top candidate genes for brain diseases, thus
generating new insight into molecular mechanisms and new targets for drug development. The large-scale integration of data will allow us to develop new pathway models in order to understand the interplay between disease markers and to inform combination therapies. We will also develop and characterise a series of new mouse
models that we will release to the academic community.
Potential applications:
End users of our research are primarily the pharmaceutical research and development communities within industry and academia. Beyond compounds and transgenic mice, EUROSPIN will also create a series of essential research reagents (e.g. antibodies) and public datasets (protein-protein interaction models). The highly advanced
European neuroinformatics community already built models at the level of neuronal networks, but synapses do
not operate independently, their influence is mediated through their role in transmitting and modulating information. Our work on the impact of specific molecules using electrophysiological recordings will provide important
parameters to bridge the persisting gap between individual synapse molecular dynamics and neuronal networks.
Eurospin has an ideal potential to identify better and more appropriate targets for therapy, give clinicians a
better understanding of the molecular basis of the disease at hand, and deliver new compound leads. More appropriate treatment through the availability of better understanding and better drugs will help to reduce the overall healthcare burden posed by neuropsychiatric disorders.
Coordinator
Nils Brose
Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.
Max Planck Institute for Experimental Medicine, Göttingen (Germany)
Telephone number: +49-551-3899725
E-mail: [email protected]
Partners
Reinhard Jahn
Max Planck Institute for Biophysical Chemistry, Göttingen (Germany)
Erwin Neher
Max Planck Institute for Biophysical Chemistry, Göttingen (Germany)
Herbert Waldmann
Max Planck Institute of Molecular Physiology, Dortmund (Germany)
Matthijs Verhage
Vereniging voor Christelijk Hoger Onderwijs Wetenschappelijk Onderzoek en Patientenzorg, Amsterdam (The Netherlands)
Noam Ziv
Technion – Israel Institute of Technology, Haifa (Israel)
Yukiko Goda
Medical Research Council, London (Great Britain)
Seth Grant
Genome Research Limited, Cambridge (Great Britain)
Erich Wanker
Max-Delbrück-Centrum für molekulare Medizin, Berlin (Germany)
Michela Matteoli
Università degli studi di Milano, Milan (Italy)
Michael Häusser
University College London, London (Great Britain)
Kobi Rosenblum
University of Haifa, Haifa (Israel)
Douglas Armstrong
The University of Edinburgh, Edinburgh (Great Britain)
Hans-Peter Lipp
Universität Zürich, Zürich (Switzerland)
Andreas Lüthi
Novartis Forschungsstiftung, Zweigniederlassung Friedrich Miescher Institute for Biomedical Research, Basel (Switzerland)
Henrik Martens
Synaptic Systems GmbH, Göttingen (Germany)
Arjen Brussaard
Synaptologics BV, Amsterdam (The Netherlands)
Troels Jordansen
Synome Ltd., Cambridge (Great Britain)
Pictures
Participants of the EUROSPIN Kick-Off Meeting, Göttingen 2010-02-10
Interactome diagram for prominent synaptic proteins causally related to human synaptopathies and some of the
current and potential future drug targets at the synapse.