EUROSPIN

European Consortium on Synaptic Protein Networks in Neurological and Psychiatric Diseases

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 Obiettivo del progetto (Objective)

'Signalling at nerve cell synapses - a key determinant of all aspects of brain function - depends on the function of 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, and 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 in reduced systems 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.'

Descrizione progetto (Article)

Mutations in genes coding for synaptic proteins are involved in the causation of neurological and psychiatric disorders, but a comprehensive understanding of the molecular processes leading to disease is still lacking. The EU-backed 'European consortium on synaptic protein networks in neurological and psychiatric diseases' (http://www.eurospin.mpg.de/ (EUROSPIN)) project aimed at improving understanding of the mechanisms leading to synaptopathies.

A multi-level systems biology approach was used to unravel the mechanisms linking mutations in genes coding for synaptic proteins to the occurrence of neurological and/or psychiatric disorders. Such an approach relies on a wide range of disciplines and techniques, spanning from biochemistry to behavioural studies. Through an improved understanding of disease causation, the consortium delivered novel leads for diagnostic tools and therapies of synaptopathies.

Scientists completed large-scale screens of protein-protein interactions (PPIs) of 1 340 synaptic proteins and generated PPI networks of 7 677 interactions. Moreover, mice lines were created that expressed tandem affinity purification-tagged synaptic proteins for several applications such as protein purification and screening of substrates. An antibody production pipeline enabled protein expression and localisation studies. In combination, these are very useful tools to study synaptic protein complexes and aberrant PPI changes in disease models.

Eighteen validated mouse lines representing different synaptopathies (e.g. SNAP-25 knockout (KO) mice for attention deficit hyperactivity disorder (ADHD)) were used to analyse synaptic transmission and plasticity as well as behaviour. Additionally, cell biological and electrophysiological studies were carried out on disease-relevant synaptic proteins such as SNAP25, Munc18-1 and NLGN-2.

An important finding was that antiepileptic drugs could be useful in ADHD treatment. Using behavioural analyses, neuronal circuits in fear conditioning were characterised to assess plasticity and learning in mice models. Interestingly, NLGN-2 KO mice were unable to acquire fear in response to certain stimuli due to reduced inhibitory synaptic transmission in the amygdala.

Studies revealed that a subset of 1 026 synaptic genes rather than an individual gene causes schizophrenia by affecting signal transduction, synaptic excitability, cell adhesion and trans-synaptic signalling. Small molecules were synthesised that affected the aggregation of beta-amyloid peptides commonly seen in Alzheimer's disease that could prove effective in therapy.

Project outcomes could now enable the synthesis of small molecules that can effectively treat synaptopathies and restore normal function. Besides placing the EU ahead in the biomedical sector, project outcomes will improve patients' quality of life while reducing the socioeconomic burdens caused by synaptopathies.