Mutant Tubulins Confer Resistance to Pathological Tau

Project Summary/Abstract Pathological tau is present in a number of age-related diseases (tauopathies) including Alzheimer's Disease (AD). With a rising aged population the prevalence of these diseases will become an enormous healthcare, economic and social burden. To-date there are no clinically proven disease altering treatments. Recently, we have discovered mutant tubulin modifies tauopathy-like phenotypes in transgenic C. elegans models, reducing human tau-induced motility deficits and neurodegeneration. We hypothesize that mutant tubulin ameliorates tau-induced phenotypes in C. elegans by altering tau-microtubule interactions. To test our hypothesis we propose to 1) use C. elegans to determine if the level of tubulin suppression is based in tubulin expression level 2) use reconstituted in vitro systems to test whether tubulin mutations affect tau- microtubule interactions and 3) use mammalian primary neurons to test whether mutant tubulin impacts microtubule properties and function. The proposed projects will elucidate the mechanisms of mutant tubulin suppression of tau induced-pathology and tau-microtubule interactions. Additionally, this work will contribute greater understanding of the cytoskeleton in neurodegenerative disease. My goal is to develop a career as a principal investigator devoted to the discovery of the molecular mechanisms underpinning tauopathies and the roles the cytoskeletal network play in neurodegeneration. To accomplish this, my training plan focuses on 1) expanding my technical toolkit to incorporate biophysical approaches and live cell imaging 2) gaining greater knowledge in the biology of aging 3) improving skills in laboratory leadership and expanding my professional network. The University of Washington and the Veterans Affairs Puget Sound Health Care System share an abundance of researchers interested in Alzheimer's and other neurodegenerative conditions. There are substantial intellectual resources such as seminars, journal clubs and meetings that create numerous opportunities broaden my perspective through interactions with the medical and scientific community in AD-related research.