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Genotypic and Phenotypic Examination of Disease Pathogenesis In C9orf72 FTD

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[Technical Report, Annual Report]

Corporate Author:

The Translational Genomics Research Institute

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Frontotemporal dementia FTD is one of the major causes of dementia in adults under the age of 65. To better understand this disease, we focus our studies on one of the most prevalent subsets of FTD patients, those carrying a mutation in the C9orf72 gene C9 FTD. To gain more knowledge about how mutations in C9orf72 lead to FTD, we are generating a genetic signature profile of postmortem patient tissues. Our studies provide first insights into C9-mediated FTD disease pathogenesis, with the goal of identifying novel therapeutic targets for future therapeutic interventions. To accomplish this goal, we generated cell type specific gene expression profiles from C9 FTD patient frontal cortex postmortem autopsy tissue samples using the novel technology of single nuclei RNA sequencing snRNA seq. This transcriptome analysis will now be compared and validated to a genotypic and phenotypic analysis of C9 FTD patient derived induced pluripotent stem cells iPSCs differentiated into cortical neurons. This cell model is currently being established after collecting and reprogramming the patient subgroup-specific iPSC lines. We will combine genetic signature profiles from these two disease models, which will then allow us to select candidate genes that we hypothesize play a significant role in C9 FTD disease pathogenesis. We have also early data on the establishment of FTD-relevant behavioral in vivo assays using Drosophila models of C9orf72. Eventually, we will test whether the aberrantly expressed genes identified from patient tissue and cells will affect the behavioral cognitive phenotypes of C9 FTD flies.

Subject Categories:

  • Medicine and Medical Research

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[A, Approved For Public Release]