Tauopathies are a family of neurodegenerative disorders characterized by the intracellular aggregation of filaments derived from hyperphosphorylated microtubule-associated protein tau. This family of neurodegenerative disorders includes Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and Pick disease, among others. Genetics, biochemical and neuropathological studies suggest that disruption of the biological function of tau proteins, either by mutations, hyperphosphorylation and/or aberrant protein interactions, may play a central role in the process of neurodegeneration. However, the molecular mechanism underlying tau-mediated neurodegeneration is still poorly understood. The JNPL3 is a transgenic mouse that expresses a human tau protein bearing a mutation (hTauP301L) commonly found in kindred with FTDP-17. The JNPL3 mice also develop behavioral and motor deficits following the accumulation of tau aggregates as early as 6-months of age. As is the case in humans, intracellular tau aggregates in JNPL3 mice are formed in an age-dependent and brain-region specific manner. Previous studies, conducted by the principal investigator (PI), were directed toward the identification of tau-associated proteins in terminally ill JNPL3 mice. Tau proteins were immunoprecipitated from terminally ill JNPL3 mice brain extract and the immunoprecipitated proteins were subjected to tandem mass spectrometry analysis. The PI identified a novel tau-associated protein that possesses calcium-binding activity. This association was validated in human temporal brain lysate from AD and FTDP-17. Herein, we refer to this novel protein as Tau-EF hand containing Associated protein (TEA). In order to further understand the physiological and/or pathological role of the association between Tau and TEA the following three research objectives will be addressed: (1) To understand the physiological role of TEA proteins;(2) To elucidate the molecular requirements for the association between TEA and tau proteins;(3) To understand the role of TEA proteins in tau-mediated neurodegeneration. The characterization of the physiological and pathological role of this novel protein and its association with tau proteins in JNPL3 mice and human brain may provide relevant information about the molecular mechanism underlying human tauopathy.

Public Health Relevance

Tauopathies are a group of neurodegenerative disorders characterized by the pathological aggregation of the microtubule-associated protein tau. The pathological events leading to the aggregation of tau proteins are still unclear. The proposed project intends to characterize the role that the novel tau-associated protein TEA plays in the development and/or progression of tau-mediated neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Enhancement Award (SC1)
Project #
5SC1NS066988-04
Application #
8292117
Study Section
Special Emphasis Panel (ZGM1-MBRS-0 (GC))
Program Officer
Sieber, Beth-Anne
Project Start
2009-08-01
Project End
2013-12-30
Budget Start
2012-07-01
Budget End
2013-12-30
Support Year
4
Fiscal Year
2012
Total Cost
$254,041
Indirect Cost
$82,541
Name
University of Puerto Rico Rio Piedras
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
143960193
City
San Juan
State
PR
Country
United States
Zip Code
00931
Vázquez-Rosa, Edwin; Rodríguez-Cruz, Eva N; Serrano, Sybelle et al. (2014) Cdk5 phosphorylation of EFhd2 at S74 affects its calcium binding activity. Protein Sci 23:1197-207
Ferrer-Acosta, Yancy; Rodriguez-Cruz, Eva N; Orange, Francois et al. (2013) EFhd2 is a novel amyloid protein associated with pathological tau in Alzheimer's disease. J Neurochem 125:921-31
Ferrer-Acosta, Yancy; Rodriguez Cruz, Eva N; Vaquer, Ana del C et al. (2013) Functional and structural analysis of the conserved EFhd2 protein. Protein Pept Lett 20:573-83