Chromatin Accessibilty and Gene Expression of Frontotemporal dementia-associated Drosophila knock-in models

ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disease associated with mutations in the microtubule binding protein Tau. The clinical presentation of FTD is heterogeneous with patients exhibiting parkinsonism, dementia, atrophy in the temporal lobes, and personality changes. Treatments are limited to mitigating the behavioral changes associated with FTD as the underlying mechanisms causing the disease are still unclear. Recent work in model systems and post-mortem tissue has shown that expression of FTD-associated Tau leads to epigenetic modifications that alter gene expression. We therefore used recently generated Drosophila knock-in models of FTD and single-cell sequencing techniques to identify chromatin accessibility and gene expression changes that are caused by specific FTD-associated Tau mutations. Comparing flies expressing wildtype human Tau (hTauWT) to flies expressing disease-associated mutant hTau (hTauK369I, hTauV337M, or hTauP301L) revealed differentially accessible regions in all cell populations, and notably many in the pericerebral fat body. One of them, Formin homology 2 domain containing (Fhos), was increased in accessibility specifically in the hTauK369I knock-in and this correlated with increased mRNA levels of Fhos. To determine a role of increased Fhos levels in FTD-associated phenotypes, we overexpressed Fhos specifically in the fat body. Overexpression of Fhos induced behavioral phenotypes in hTauK369I and, at a later age in the wildtype background and in hTauWT. In contrast, reducing Fhos levels induced phenotypes in hTauWT but had no effect on hTauK369I expressing flies. Together this supports that increased Fhos levels in the fat body could promote detrimental effects in hTauK369I.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE303812 | GEO | 2026/07/31

REPOSITORIES: GEO