A hallmark feature of Alzheimer?s disease (AD) is the accumulation of neurofibrillary tangles that are composed of the microtubule-associated protein Tau. Moreover, aggregates of this protein are found in a variety of other neurodegenerative diseases, together referred to as Tauopathies, underscoring the central role of this protein in the pathogenesis of these neurodegenerative diseases. Although originally identified as a microtubule- binding protein, Tau has now been connected with a variety of functions and accordingly it has also been localized to various cellular compartments, including the nucleus. In AD patients, Tau can form paired helical filaments in the nucleus and its function in the nucleus, as in other compartments, seems to be regulated by phosphorylation. Loss of Tau results in a decrease of heterochromatin and changes in heterochromatin, chromosomal mis-segregations and aberrations have been described in AD patients. Furthermore, Tau can protect DNA from damage induced by radiation, radical formation, or stress and again DNA damage is also observed in AD patients. However, Tau may also actively regulate transcription. In addition to binding to double- stranded DNA in a sequence-independent way, Tau can bind to single stranded DNA in a sequence-specific manner, suggesting that it might interact with transcriptional complexes to regulate transcription. However, at this time it is still widely unknown how disease-associated changes in Tau affect these functions and how this could contribute to the pathogenesis. Using novel human Tau knock-in Drosophila models, we found that two Tauopathy-causing mutation in Tau, hTauV337M and TauK369I, lead to increased vulnerability to radiation and age- induced DNA damage. Furthermore, they increase heterochromatin formation in comparison to knock-in flies expressing normal human Tau. We therefore propose to use these models to address the hypothesis that the increased DNA damage triggers cell cycle re-entry of neurons that then results in apoptosis or cellular senescence, providing a mechanism for the neurodegeneration and behavioral deficits we observed in these models. In addition, we will perform sequencing experiments to determine how this alters chromatin accessibility and the neuronal transcriptome. Defining mechanisms and pathways that are affected by changes in the nuclear functions of disease-associated Tau could provide critical new insight into the underlying causes of Tau pathologies, which in turn can be used to develop treatment strategies. Public Heath Relevance: Although it is well-known that Tau plays a crucial role in the pathology of Tauopathies, the recent findings that Tau is a multifunctional protein with many other functions than microtubule-binding, has opened a new avenue for identifying mechanism causing or contributing to these diseases. In this proposal, we are focusing on nuclear functions of Tau and how their disruptions may cause neuronal dysfunctions and changes in the transcriptome. This may therefore identify novel targets for developing treatment strategies that can prevent or delay the progression of these diseases.
Tau is a multi-functional protein that plays a crucial role in several neurodegenerative diseases, including Alzheimer?s disease. One of the more recently identified functions of Tau is regulating chromatin structure and transcriptional regulation; however, how disruptions of these function contribute to the pathology of the diseases is still mostly unknown. To address this gap in knowledge, we will use our novel Drosophila knock-in models to investigate effects of disease-associated Tau on DNA damage responses, chromatin structure, and the neuronal transcriptome.
