Effects of frontotemporal dementia-associated Tau mutations on nuclear organization in a Drosophila melanogaster human tauopathy model

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PROJECT SUMMARY: Frontotemporal dementia (FTD) is a neurodegenerative disease associated with mutations in the microtubule binding protein Tau. Average age of FTD onset is 49 years old with a life expectancy of 8.5 years. The clinical presentation of FTD is heterogeneous with patients exhibiting parkinsonism, dementia, atrophy in the temporal lobes, and personality changes. Current treatments can mitigate aspects of the behavioral changes associated with FTD, however, no therapies are available to slow the progression. Since patient sample procurement is restricted to post-mortem tissue, our understanding of the progression and underlying pathogenic mechanisms of this disease is limited, and to address these issues requires the use of model organisms. Recent work in model systems and post-mortem tissue has shown that expression of FTD-associated mutant Tau may lead to epigenetic modifications that alter gene expression. In our lab, we model FTD using Drosophila, which allowed us to conduct longitudinal studies to observe FTD progression throughout the adult lifespan. This revealed that adult Drosophila expressing FTD-associated mutant human Tau (hTau) have age-dependent neurodegenerative vacuoles, axonal changes, locomotion defects and impaired memory while flies expressing normal hTau did not. This confirms that our models show pathogenic phenotypes associated with Tauopathies and it provides the basis to now use these models to identify molecular mechanisms of pathogenicity. In this proposal, I hypothesize that FTD mutant Tau alters heterochromatin distribution, which disrupts gene expression and chromatin structure producing or contributing to the behavioral and neurodegenerative phenotypes seen in FTD pathology. In addition, I hypothesize that the gene regulatory networks will vary depending on the FTD mutation as each mutation is clinically distinct. I propose to test this hypothesis with the following aims: (1) Use single-cell omics to assess how human Tau FTD mutations alter chromatin accessibility and gene expression in the young and aged adult Drosophila brain, (2) Probe nuclear architecture changes by mapping heterochromatin regions in the hTauK369I FTD Drosophila model, (3) Determine the role of novel candidate genes in our FTD Drosophila model through genetic interaction tests. Utilizing single-cell technology will allow us to understand how the mutant Tau affects distinct cell types in the brain and it may identify cell-type-specific candidates, and lead to the development of targeted therapies.