DESCRIPTION (provided by applicant): This proposal will enable the applicant to become an independent researcher in the field of inherited neurodegenerative disorders. It builds upon the candidate's background in aging research and implements a comprehensive career development plan that aims to 1) expand the breadth of research skills in the area of cell biology and genetics and enhance current research skills, 2) fill knowledge gaps in the understanding of cellular pathways in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and 3) result in publications and academic leadership development. The research will be conducted at the UCLA Department of Neurology with excellent institutional support and opportunities to collaborate. The mechanisms by which mutant tau causes neurodegeneration in FTDP-17 - a group of inherited dementias linked to mutations of the microtubule-associated protein tau - are poorly understood, thereby representing a major knowledge gap in the understanding of cell death pathways in degenerative dementias. The goal of the project is to fill this knowledge gap by focusing on one candidate mechanism, by which tau misexpression may lead to neurodegeneration. We identified this mechanism in previous studies of a Drosophila model of human tau expression. The Aims focus on studies that verify and extend preliminary findings suggesting that GSK-3-beta and beta-catenin, both components of the Wnt signaling pathway, exacerbate mutant tau-induced neurodegeneration related to FTDP-17. Preliminary results suggest that beta-catenin accumulates in CNS regions vulnerable to neurodegeneration and that GSK-3-beta may be sequestered by mutant tau. The applicant will investigate the overall hypothesis that the most common tau mutation, P301L, interferes with the ability of GSK-3-beta to phosphorylate beta-catenin and that the resulting stabilization of beta-catenin triggers enhanced neuronal death. Specifically, correlations of the onset of beta-catenin accumulation and cell death will be addressed. GSK-3-beta activity and association with mutant tau that may lead to beta-catenin accumulation and neurodegeneration will be explored. The proposed biochemical and cell biological studies will initially utilize transgenic mice expressing mutant P301L tau, which model aspects of FTDP-17 clinically and pathologically. Once correlative studies have provided information regarding potential interactions of mutant tau, GSK-3-beta and beta-catenin, functional studies of these interactions are planned.