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Project Topic
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Polyglutamine diseases are a group of 9 neurodegenerative diseases caused by over-repetition of the CAG codon, which translates into polyglutamine tracts within specific proteins for each disorder. Despite important progresses in the knowledge of the pathological mechanisms involved we still miss effective therapies. Advances in this field depend on innovative, predictive, models of disease for which there is an urgent need for both mechanistic and preclinical studies. In this proposal we focus on 3 polyglutamine (polyQ) disorders: Huntington’s disease, and spinocerebellar ataxias type 3 and 7. We propose to a) generate novel, improved disease models, b) to thoroughly characterize and compare both these and previously generated models and, c) to standardize, reproducible methodologies to investigate pathomechanisms that present commonalities between polyQ diseases. We will concentrate on the leading models, namely the genetically-modified rodent models and the induced pluripotent stem cells (iPSC). The first have been and are instrumental in the progression of the field, while the latter offer the promise of enabling major ground-breaking advances. Specifically, we will: 1) generate and implement for the 3 disorders novel iPSC, based on genetically engineered isogenic lines and optimized, reproducible neuronal and glial differentiation protocols (WP1), 2) generate and characterize genetically-modified rat and mouse models and provide a comprehensive phenotypic analysis of pathophysiological parameters (WP2), 3) develop and implement standardized, robust medium/high throughput methodologies for quantitative analysis of specific defects for iPSC and neuronal models (WP3), 4) develop in vivo harmonized phenotypic readouts for the use of animal models in different centers and assay of the polyglutamine-expanded protein (WP4), and finally, 5) develop integrated investigation of pathological mechanisms focusing on transcriptional analysis of iPS derived neurons and animal tissues (WP5). This project is an ambitious, innovative, multi-national and multi-disciplinary collaborative research project aligned with the objectives of Topic 3 (Advanced animal or cell experimental models of neurodegenerative diseases) of this JPND call and brings together an international and interdisciplinary consortium of neurobiologists, biochemists, biotechnologists and neurologists that are among the leading European groups in the field of polyglutamine diseases, and will provide a unique set of complementary, high-level competences that enable us to reach the proposed aims. All of the partners coordinate and/or take part in other major European initiatives on stem cell research and animal models research for polyQ diseases, which allows an effective cross-fertilisation, increased impact and facilitated implementation of standards for the proposed work, other European projects and will allow us to set new high standards for the use of iPS cells and transgenic animal models. We expect that this project can make a truly important contribution to the field of polyglutamine diseases by providing the models and methodologies to enable significant advances in a) the knowledge of the mechanisms of these diseases and b) provide the tools for pre-clinical identification and validation of new effective therapies for polyglutamine disorders.
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