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Understanding the Role of TSC1/2 in Cerebellar Purkinje Neurons

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Children's Hospital Boston Boston United States

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Tuberous sclerosis complex is a rare multisystem disorder caused by mutations in either TSC1 or TSC2 genes. Neurological manifestations of TSC include epilepsy, cortical tuber formation and increased prevalence of autism in the patients. Previously our group has shown that Tsc1 knock-out mice Purkinje cells are involved in the development of autistic-like features for these mice. In this study we have developed differentiation protocol for generation of human Purkinje cells PCs from hiPSCs derived from TSC-patients with heterozygous TSC2-mutations. We have studied mTOR-pathway hyperactivation in TSC2-deficient patient hiPSC-derived PCs compared to control cells and characterized the transcriptional profiles of the TSC2-deficient human PCs in vitro. We have also created an isogenic control hiPSC-lines with correction of the heterozygous TSC2-microdeletion in TSC-patient derived hiPSCs. To study TSC2-deficits in the isogenic human cells we have characterized the cerebellar precursor cell development and PC differentiation of the isogenic control hiPSC-clones in parallel with TSC2-deficient isogenic patient derived cells. Transcriptional profiling and characterization of the disease phenotypes of the TSC2deficient hiPSC-derived PCs may discover interesting targets for the future development of pharmacotherapy for TSC-patients with autism.

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Technical Report,01 Sep 2016,31 Aug 2017



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