Modelling cerebellar pathology of Ataxia-Telangiectasia: Assessing ATM-deficient mice versus human iPS cells

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Ataxia-telangiectasia (A-T) is caused by mutations in the ataxia-telangiectasia mutated (ATM) gene, which manifest in an autosomal recessive multi-system disorder, including neurological dysfunction. The best-studied function of ATM is a master controller of signal transduction for DNA damage response. However, additional and thus far poorly understood functions of ATM likely play critical roles in the neurodegenerative phenotype of A-T. Understanding the molecular basis of many diseases, including A-T, has been hampered by the lack of appropriate in vivo (animal) and in vitro (cell culture) models that accurately reflect the disease phenotypes. Importantly, reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) followed by generation of disease-relevant cell types in vitro provides an opportunity to gain insight into the molecular and cellular basis of disease. Neurological disorders in particular can greatly benefit from iPSC-disease modeling, because cell types of the central nervous system, such as neurons, are typically available only from post-mortem samples.In this project the two applicants build upon their complementary expertise (1) in mouse brain OMICS-level analysis of ataxia pathways affecting Purkinje neuron function and (2) in advanced genetic engineering of iPSCs. The aim of this project is to gain detailed insight into the cellular pathways affecting the neurodegenerative phenotype associated with A-T.Organotypic slice cultures established from Atm-/- mice will be employed to address DNA- and oxidative damage-induced cellular neuroinflammation and autophagy changes, as well as synaptic functions of ATM. Furthermore, transcriptome and proteome analyses of cerebellar samples of Atm-/- and wild-type mice will enable us to discover and annotate novel pathways and markers associated with neuronal functions of ATM in an unbiased manner. In parallel, isogenic pairs of patient-derived iPSC lines and their genetically corrected counterparts will be established for modeling A-T. The isogenic pairs of cell lines will be used to derive neuronal progenitors and characterized in vitro. The output of this project will provide valuable insights into the pathway mechanisms of disease, and cell-based models to investigate A-T-associated neurodegeneration, which may provide novel targets for future therapies.