Medical Research

University of California, Santa Barbara

Songi Han, Kenneth Kosik, Joan Shea, Scott Shell
Santa Barbara, CA
$1,000,000
June 2020

The aggregation of the abundant neuronal protein tau into neurofibrillary brain deposits is directly diagnostic of a large family of neurodegenerative human diseases.  These are collectively known as tauopathies and include Alzheimer’s Disease.  Stunning new cryo-electron microscopic images of tau fibril structures from post-mortem tauopathy patients now define the fibril shape with atomic resolution that uniquely identifies different tauopathies.  However, none of these pathological fibrils have ever been replicated in the laboratory, which is a prerequisite for developing therapeutic strategies.  Current drug developments for tauopathies operate under the premise that pathological tau fibrils serve as competent seeds to “infect” native tau and transmit their disease-defining shape from cell to cell.  However, the fundamentals of this premise are entirely unknown.  A team of University of California, Santa Barbara investigators, consisting of a computational biophysicist, an engineer, a spectroscopist and a neurobiologist, will join their unique expertise to uncover the biophysical and molecular bases for tau aggregation and fibril shape transmission.  Questions to be addressed include the identity and composition of competent seeds and the mechanisms of protein shape transmission from mother to daughter fibrils.  The team’s ambitious endeavor is to establish a new paradigm of dynamic pathway design to control protein shape transmission along a defined aggregation pathway, challenging decades of focus on static end-fibril structures.  Answering these research questions will, at last, place the testing of therapeutic strategies for tauopathies on a firm scientific foundation.  It will also transform our ability to tune the shape of other fibril-forming proteins critical to numerous diseases and functions.

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