Abstract

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are tauopathies characterized by selective vulnerability of neuronal subpopulations to tau aggregation, leading to cellular dysfunction and death. Although this selective vulnerability has long been recognized, its cause is unknown. The transcription factor RORB has emerged as a potential contributor, as its expression correlates with vulnerable neurons in post-mortem tissue from AD and FTD patients. However, it remains unknown whether RORB is causative of this vulnerability. I hypothesize that RORB drives the selective vulnerability of neuronal subtypes in FTD by regulating cellular stress responses. This research aims to comprehensively investigate the role of RORB in tauopathies using human induced pluripotent stem cell (iPSC)-derived neurons and a mouse model of tauopathy. As a transcription factor, RORB likely regulates an extensive gene network; thus, I will identify RORB target genes in iPSC-derived neurons with an FTD-causing tau mutation and assess their impact on tau pathology and neuronal survival. Moreover, I will extend the study into an in vivo context, assessing the therapeutic potential of RORB for selective vulnerability in a mouse model of tauopathy. This multifaceted approach combines cutting-edge CRISPR-based functional genomics, iPSC technology, and in vivo manipulations to unravel the intricate molecular mechanisms underlying the selective vulnerability of neurons in tauopathies. The identification of a functional driver of selective vulnerability will advance our understanding of molecular mechanisms that could inform novel treatments for Alzheimer’s disease and frontotemporal dementia.