Tau is a microtubule-associated protein that is the primary component of the neurofibrillary tangles that are a hallmark of Alzheimer's disease. Tau modulates the stability of neuronal microtubules and it is generally thought that modifications to tau associated with disease disrupt tau-microtubule interactions, which can in turn affect proper motor-based cargo trafficking in axons. Despite intensive study, a detailed understanding of the biophysical basis of tau's interaction with and influence on microtubule assembly dynamics is lacking. Therefore, our goal is to develop a molecular level understanding of this mechanism and determine how tau aggregation and microtubule assembly dynamics are altered by disease-associated tau variants. We have developed the hypothesis that disease-associated modifications to tau primarily affect its interactions with tubulin, manifested in vivo as altered microtubule assembly dynamics and loss of microtubule stability. To investigate this hypothesis, we have developed two specific aims with the following goals: assessing the impact of disease-associated variants of tau on interactions with tubulin and microtubules (Aim 1); determining the impact of tau variants on microtubule assembly and dynamics (Aim 2). In order to achieve these goals, we will use in vitro experimental analysis of purified proteins, live cell imaging of tau interaction with single microtubules, and computational modeling at the molecular and cellular levels to create a more detailed biophysical picture of tau function. Through this research, we expect to develop a cellular systems-level understanding of the molecular factors that alter native tau-tubulin/microtubule interactions to result in neurofibrillary tangle formation and loss of normal microtubule assembly dynamics. We expect that our studies will lead to biophysics-based prediction of cellular-level phenotypes from tau genetic sequence information, which will then serve to rationally guide therapy development toward target(s) that restore normal tau-microtubule dynamics and self-assembly.

Public Health Relevance

Loss of function of the microtubule associated protein tau leads to microtubule destabilization, consequent disruption of normal trafficking of cellular components, and is one of the major hallmarks of Alzheimer's disease. Here, we seek to develop a detailed molecular model of tau-mediated polymerization of tubulin and to understand of how these normal interactions are altered by mutations to tau found in disease. As one rational approach to drug design would be to alter tau-tubulin or tau-microtubule interactions, our work may provide a framework for understanding the structural features of tau to be targeted for therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG053951-01
Application #
9192256
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (56)R)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2016-07-15
Project End
2021-06-30
Budget Start
2016-07-15
Budget End
2021-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$2,739,985
Indirect Cost
$398,125
Name
University of Pennsylvania
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Melo, Ana M; Coraor, Juliana; Alpha-Cobb, Garrett et al. (2016) A functional role for intrinsic disorder in the tau-tubulin complex. Proc Natl Acad Sci U S A 113:14336-14341