GENCODYS

Genetic and Epigenetic Networks in Cognitive Dysfunction

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 Obiettivo del progetto (Objective)

'Mutations in about 400 different genes have been associated with Cognitive Disorders (CD), such as mental retardation, autism, neurodegenerative disorders, and psychiatric disorders. Whereas CD impose a major medical and socio-economical problem, there are no systematic studies that aim to provide insight into common mechanisms in CD. We propose a systems biology approach to gain insight into common mechanisms leading to cognitive impairment: (1) Identification of genes involved in cognitive disorders. Despite considerable progress in the identification of genes underlying CD, the majority of causative genes in CD remain unidentified. Therefore, our first objective is to identify new genes causative of CD by implementing high-throughput strategies. (2) Elucidation of molecular networks that are commonly disrupted in CD. Recent genetic and neurobiological research revealed evidence for a number of molecular and cellular pathways that are shared by the various genetic CDs. Prominent examples are Rho GTPase-related genes and genes that regulate chromatin structure/function (epigenetics) associated with mental retardation and autism. Our second objective is to systematically explore this concept by elucidation of molecular networks using functional genomics strategies in genetic models that are the cornerstone of neuroscience, such as mouse and fruit fly. (3) Identify genetic modifiers and small compounds that modulate the disease phenotype. Our third objective is to resolve the molecular underpinnings of the large degree of clinical variability that is typical for all types of CD, even among patients carrying identical gene mutations. Genetic modifier screens in cultured primary neurons as well as in available Drosophila models for CD will be used to reveal phenotypically relevant genetic interactions and molecular networks. Moreover, drug screens shall be conducted in fly and cellular models for CD, which will lead to pharmacological rescue of mouse models.'

Introduzione (Teaser)

Despite identification of more than 400 genes involved in cognitive disorders (CDs), the molecular basis of early-onset CD remains largely unknown. Using a systems biology approach, European researchers are uncovering key molecular networks that are commonly disrupted in neurodevelopmental disorders, such as intellectual disabilities (IDs), autism spectrum disorder (ASD) and schizophrenia.

Descrizione progetto (Article)

At the end of the fourth phase, the 'Genetic and epigenetic networks in cognitive dysfunction' (http://www.gencodys.eu (GENCODYS)) project has already achieved many of its objectives. A cohort of more than10 000 patients has been established and targeted sequencing and sequencing of whole exomes has confirmed and revealed many candidate genes for intellectual disability disorder and ASD. Gencodys has identified over 100 new genes with a recessive mutation co-segregating with the cognitive disease phenotype.

Imaging and behavioural assays of wild type and genetically manipulated flies (Drosophila models) have lend support to the causality of mutations in hundreds of novel and known genes involved in CDs. Similarly, over 40 mouse models, each carrying a mutation which is present in human CD, have been generated and are being studied by in-depth phenotyping. Importantly, these cross-species investigations have revealed that the molecular basis of key processes in cognition appear to be evolutionary conserved.

On a broader basis, how genes contribute to structure and function of the nervous system, neurogenomics occupied a work package of its own. Transcriptome and epigenomic profiles have been developed for the mutations involved in CDs, corresponding to the previous mentioned mouse models. The functions of the proteins expressed and their roles in synaptic function and nerve morphology have also been outlined.

GENCODYS researchers have drawn interesting parallels between human CD genes and their respective versions in mouse and Drosophila. For example, Drosophila eye phenotypes, at multiple levels, correspond to human CD phenotypes.

Project research has featured in many high-impact journals such as Nature Genetics, Nature Neuroscience, Science and The New England Journal of Medicine. A highly successful GENCODYS conference held in Cyprus further disseminated project results. Furthermore, GENCODYS aims to stimulate knowledge transfer between patients and research by patient representatives meetings held in several countries.

Intellectual disabilities account for 10 % of total health care expenditure in most European countries. GENCODYS research is helping to establish exactly which molecular networks are frequently disrupted in a range of CDs. As a result, many new target compounds can be further investigated for their therapeutic potential.