? Progressive supranuclear palsy shares its defining pathologic signature, neurofibrillary tangles (NFT) consisting primarily of hyperphosphorylated tau, with numerous neurological diseases, including Alzheimer's disease, corticobasal degeneration, Pick's disease as well as frontotemporal dementia and Parkinsonism linked to chromosome 17. To improve our understanding of the mechanism underlying NFT formation and its functional impacts we have developed cellular models that produce tau filaments with morphological and biochemical characteristics of human tauopathies. The models consist of conditional transfectants generated from human neuroglioma [H4] and neuronal [BE(2)-M17D] cells in which transgenic production of wild-type or mutant tau is regulated via the TetOff inducible mechanism. Preliminary studies demonstrated that treatment of these cells with 4-hydroxynonneal (HNE), proteosomal or calpain inhibitors enhances the assembly of disulfide-linked tau aggregates. The results suggest that cellular insults such as oxidative stress and deregulation of proteases may play a role in the formation of NFT. We will employ this cellular model to uncover the molecular mechanism underlying tau aggregation induced by various insults.
The Specific Aims of our proposal are: (1). To test if factors implicated in the etiology and pathogenesis of human tauopathies exacerbate tau aggregation in conditional transfectants, (2). To determine if the enhanced aggregation is associated with changes in tau solubility/partition, phosphorylation, degradation and oligomerization, (3). To investigate whether such exacerbated tau aggregation is associated with altered level or state of activation/activity of particular kinases, proteases and/or proteasomes, and (4). To study if progression of the exacerbated assembly of tau aggregates can be blocked through deregulating kinases/proteases. The results are likely to provide valuable information for a rational design of therapeutics to treat neurofibrillary degeneration. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048052-02
Application #
6948775
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Murphy, Diane
Project Start
2004-09-15
Project End
2009-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$277,500
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
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Hamano, Tadanori; Gendron, Tania F; Causevic, Ena et al. (2008) Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci 27:1119-30
Ko, Li-Wen; Kulathingal, Jayanarayan G; Yen, Shu-Hui C (2007) Cytosine beta-D-arabinofuranoside used as a paradigm modifier to increase production of tau aggregates in a cellular model of tauopathy. Neurochem Res 32:823-32
DeTure, Michael; Granger, Brian; Grover, Andrew et al. (2006) Evidence for independent mechanisms and a multiple-hit model of tau assembly. Biochem Biophys Res Commun 339:858-64