Inter-University Attraction Poles Phase VII P7/16 Network: An integrated approach towards understanding the pathogenesis of neurodegeneration

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Identifying novel gene mutations and genetic risk factors

These attempts will be targeted to the study of AD, PD, FTLD, ALS where many genes and risk factors are still unidentified. Rare highly penetrant disease mutations and common risk factors will be identified by state-of–the art molecular genetics and genomic approaches.

Developing new cellular and animal models

We will develop new cellular and animal models for the study of the diseases in the project. This will include the knock-down, classical overexpression and knock-in of new disease causing genes, mutations or modifiers in cellular systems, in rodents models, in drosophila and in zebrafish. Viral vectors expressing these disease causing genes or modifiers will also be implemented. We will particularly focus on knock-in models using zinc finger technology to make precise deletions or mutations, avoiding as much as possible classical overexpression models.

Screen for genetic modifiers in small model organisms

Drosophila and zebrafish models will be used to identify modulators of known and new disease causing mutations in neurodegenerative diseases, and the effects of risk factors genes identified by GWA studies.

Perform functional studies into pathogenetic mechanisms

Functional cell biological assays will be developed to analyze the effects of genes, mutations and modifiers on pathogenetically relevant read-outs in the context of AD, FTLD, PD and ALS. Human neuropathology will be a key aspect in relation with disease models. Already available transgenic mouse models for key proteins will be shared among members of the consortium. Available and new transgenic mouse models will be further analyzed by biochemistry, neurochemistry, neuropathology, and cognition and behavioural batteries. Biophysical analysis of protein aggregation and aggregation-specific protein interactions will also be a central theme as it involves many of the neurodegenerative diseases proposed to be studied here. We will validate the results of cell biological assays in biosamples (ideally brain) and eventually iPS cells of patients carrying the pathogenic variant versus control individuals. For instance, Western blot analysis will be used to evaluate the effect of mutations on expression and metabolism of the protein and neuropathological examination of patients’ brain will be done to study localization.

Translating findings from basic research into markers for early diagnosis and disease progression

A major goal of this application is to provide a coordinated, interdisciplinary research program along with novel technologies to support network members pursuing translational research directly involving Alzheimer, Parkinson, FTLD and ALS patients or laboratory models of these pathologies. In this way, the network is both involved in the generation of knowledge and provider of the instruments to validate the knowledge and participate in the exploration of the development of new tools of intervention, whether for early diagnosis or therapy. This will be helped by pursuing the construction of high-quality biobanks of biological samples and postmortem tissue from patients, with well-documented neuropathological and clinical data and findings from imaging and biochemical makers. Several groups in the consortium will be involved in imaging and early diagnosis of neurodegenerative disorders. The researchers in this network are among the world leaders in elucidating the underlying mechanisms of these diseases, but also involved in the development of new methods to accurately predict and diagnose the diseases, creating new treatments and actively participating in clinical trials. Our network in addition benefits from being part of a conglomerate of prestigious universities, allowing our researchers to collaborate with leaders in other disciplines and therefore facilitating creativity to their work. Hence, one can see the translational potential of our network in the following crucial aspects of neurodegeneration: i) improving diagnosis, ii) preventing and treating neurodegeneration, iii) educating the new generation of scientists and improving the working conditions of those in their early stages of their careers.