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| Dissertation / PhD Thesis | DZNE-2025-01283 |
2022
Abstract: Mutations in genes that control epigenetic gene expression, especially the machinery that controls Histone 3 lysine 4 (H3K4me) methylation, are over-represented in intellectual disability disorders. It is mediated by both lysine methyltransferases and demethylases. Dysregulation of these enzymes is closely associated with cognitive dysfunction in humans. Moreover, there is evidence that H3K4me3 levels decrease in neurodegenerative diseases such as Alzheimer’s disease and previous studies demonstrated that H3K4me demethylases (KDMs) are important targets for cognitive functions. In the first study, we specifically tested the therapeutic potential of H3K4me demethylases (KDMs) in vitro and in vivo. Our data suggest that decreasing the levels of KMD5B can improve neuronal synapse plasticity and reduce inflammatory responses. When we downregulated the KDM5B in aged mice, it helps to rescue their learning and memory abilities. Furthermore, inhibition of KDM5B in mouse models for age-associated memory decline or amyloid deposition also ameliorated memory impairment. Our data strongly suggest that H3K4me demethylases, represented by KDM5B, have great potential to become therapeutic targets for the treatment of cognitive disorders. Additionally, Frontotemporal degeneration is the second most common type after Alzheimer’s disease, sharing pathophysiological mechanisms and genetic origins with some dementia-specific disorders. Mining FTD-associated microRNAs can be used to distinguish FTD from other dementia-specific disorders. Thus in the second study, we established an in-depth smallRNAome sequencing analysis of frontal and temporal cortex tissue to identify specific microRNAs that showed dysregulation in a group of FTD patients. Further analysis was performed by manipulating one of these signatures, miR-129-5p, to reflect the molecular changes that occur during brain pathology in vitro. The impact of inhibition of miR-129-5p markers on cognitive impairment was also revealed in animals, suggesting its use as a powerful pathogenetic indicator of FTD-related disorders.
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