Real-time imaging and mechanistic analysis of Tau fibril disaggregation in live cells

ended

Age-dependent neurodegenerative diseases associated with protein aggregation represent one of the most important medical and socio-economic challenges of our time. With the extension of human life span, the prevalence of this group of diseases has markedly increased. Among them, Alzheimer’s diseases (AD) and other dementias have become the second leading cause of death in high-income countries. As a pathological hallmark, Tau amyloid aggregation in the brain has been determined to be closely related to the cognitive impairment in AD and related dementias. Despite major research efforts world-wide, the mechanism of Tau pathology and how its manifestation is prevented in healthy cells is not yet understood. This project builds on recent findings in the host laboratory that the AAA+ ATPase complex of VCP can mediate the disaggregation of Tau fibrils in a cellular model. Consistently, autosomal dominant VCP hypomorph mutations have been found to exacerbate Tau pathology in patients. I will use live cell fluorescence imaging and advanced single-molecule tracking to investigate the mechanism of VCP and cooperating factors in Tau disaggregation in real time. Stable reporter cell lines will be generated in which components of interest carry self-labeling affinity tags to introduce fluorescence signals for single-molecule monitoring. The planned research will provide new insights into the cellular pathways of fibril decomposition and may benefit the development of new therapeutic strategies for tauopathies. The experimental approach to be established in this study can be applied to investigate disaggregation in other neurodegenerative disorders, including Huntington’s and Parkinson’s disease.