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.

Grant Number: 5R00AG073455-05
NIH Institute/Center: NIH
Principal Investigator: Sarah Benbow