Research Projects

Neurodegenerative tauopathies, such as Parkinson's, Frontotemporal dementia, and Alzheimer's disease, are devastating human disorders with unexplored mechanisms and no effective therapies. The conversion of physiological tau proteins into pathogenic forms due to hyperphosphorylation and their accumulation in brain neurons as neurofibrillary tangles (NFTs) have been considered a trigger for disease pathogenesis. However, recent evidence shows a strong correlation between disturbed immune response and neurodegeneration. A significant number of immune response genes were abnormally expressed in animal models of tauopathies. The study hypothesizes a dynamic involvement of the immune response Toll-pathway in tauopathies. Toll-pathway is a key signaling cascade that plays a critical role in pathogen recognition and cellular immune response initiation. A preliminary genetic screening was performed using Drosophila models of human tauopathies, and it was found that tissue-specific downregulation of GNBP3 dominantly suppresses human tau-mediated neurodegeneration. This suggests a critical involvement of the immune response Toll-pathway in the pathogenesis of human tauopathies. The research proposal aims to identify and characterize candidate Toll-pathway candidates that could be used as druggable genetic modifiers to restrict tau pathogenesis. A comprehensive study will be conducted to decipher the underlying cellular and molecular mechanisms driving the Toll-pathway-mediated rescue event against human neurodegenerative tauopathies. The study will use classical and contemporary genetic, cellular, and molecular biology approaches to achieve its objectives.