Abnormal tau is a common feature of several age related neurodegenerative diseases. In Alzheimer's disease tau forms neurofibrillary tangles, that along with amyloid plaques, comprise the major neuropath- ological features of the disease. In several frontotemporal dementias, tau is mutated. Also, in other fronto- temporal dementias as well as in progressive supranuclear palsy and corticobasal degeneration, only specific isoforms of tau are featured in the neuropathology. The mechanisms by which neuronal cells die in these diseases is unknown. Our research focuses on a new interaction for tau that identifies tau as a signal transduction protein. As a binding partner for the SH3 domain of src family tyrosine kinases, we have found that tau is tyrosine phosphorylated and is capable of up-regulating kinase activity. Our preliminary data also shows that disease related structural modifications in tau increase its affinity for the SH3 domain of fyn. Therefore, we hypothesize that the interaction between tau and fyn is a critical event in the neurodegenera- tive process.
The specific aims of this proposal will 1) use animal models for frontotemporal dementia and Alzheimer's disease to investigate the temporal and spatial appearance of tyrosine phosphorylated tau relative to other neuropathological features;2) further our knowledge of the tyrosine kinases that act on tau; 3) extend our analysis of the interaction between disease related isoforms of tau and the SH3 domain of fyn; 4) elucidate the structural basis for the differential SH3 binding ability of four repeat versus three repeat tau; and 5) investigate the functional consequences of up-regulated src family tyrosine kinase activity in neuronal cells, focusing on cell cycle characteristics and susceptibility to apoptosis. Our working model is that phosphorylated 4R tau and/or tau FTDP-17 missense mutants have an increased ability to up-regulate fyn and/or src activity. In neurons, this increase in tyrosine kinase activity would result in the activation of signal transduction pathways, such as those involved in cell division or apoptosis, that eventually lead to cell death. This model is consistent with a gain of toxic function for tau and the autosomal dominant aspect of FTDP-17 mutations. The identification of the fyn-tau interaction as a critical event in the neurodegenerative process would suggest new candidate targets for therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017753-10
Application #
7796654
Study Section
Special Emphasis Panel (ZRG1-MDCN-F (02))
Program Officer
Miller, Marilyn
Project Start
1999-05-01
Project End
2012-02-28
Budget Start
2010-03-15
Budget End
2012-02-28
Support Year
10
Fiscal Year
2010
Total Cost
$253,246
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Lee, Gloria; Leugers, Chad J (2012) Tau and tauopathies. Prog Mol Biol Transl Sci 107:263-93
Bhaskar, K; Hobbs, G A; Yen, S-H et al. (2010) Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy. Neuropathol Appl Neurobiol 36:462-77
Leugers, Chad J; Lee, Gloria (2010) Tau potentiates nerve growth factor-induced mitogen-activated protein kinase signaling and neurite initiation without a requirement for microtubule binding. J Biol Chem 285:19125-34
Bhaskar, Kiran; Yen, Shu-Hui; Lee, Gloria (2005) Disease-related modifications in tau affect the interaction between Fyn and Tau. J Biol Chem 280:35119-25
Lee, Gloria; Thangavel, Ramasamy; Sharma, Vandana M et al. (2004) Phosphorylation of tau by fyn: implications for Alzheimer's disease. J Neurosci 24:2304-12