Disturbance of the dynamic balance between protein tyrosine phosphorylation and dephosphorylation is crucial for the development of many serious conditions, including cancer, diabetes, and autoimmune disorders. This is the first time that tyrosine phosphatase inhibitors are being proposed to improve cognitive function in Alzheimer's disease (AD). STriatal-Enriched Phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that is highly expressed in regions where consolidation of memory occurs and regulates the internalization of NMDARs. Our recent work demonstrates that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Moreover, using genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model, we showed that a decrease in STEP levels attenuates the cognitive and cellular deficits observed in six-month old 3xTg-AD mice. The hypothesis that STEP inhibitors may prove therapeutic for the treatment of AD is a shift in the current paradigm of reducing Abeta levels to inhibiting a downstream target of Abeta. The recent failure of the gamma-secretase inhibitor semagacestat in phase III clinical trials suggests that other approaches are clearly needed. This proposal seeks to generate the first STEP-specific inhibitors. Besides a screening ready HTS assay, we also have a secondary assay, profiling assays, as well as cell-based and in vivo assays in place to verify, characterize, and prioritize hits. We have milligram amounts of highly pure STEP in hand, so that HTS for STEP inhibitors could commence immediately.

Public Health Relevance

The goal of this proposal is to seek access to high-throughput chemical library screening to identify hit compounds for the STriatal-Enriched Phosphatase (STEP), which we will then further develop into potent and specific inhibitors of STEP. Protein tyrosine phosphatases have been recently implicated with numerous human diseases. This is the first time that tyrosine phosphatase inhibitors are being proposed to improve cognitive function in Alzheimer's disease. Our recent data suggest that STEP inhibitors may prove therapeutic for this devastating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
5R03MH095532-02
Application #
8306030
Study Section
Special Emphasis Panel (ZRG1-BST-F (50))
Program Officer
Yao, Yong
Project Start
2011-07-22
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$48,750
Indirect Cost
$23,750
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Xu, Jian; Chatterjee, Manavi; Baguley, Tyler D et al. (2014) Inhibitor of the tyrosine phosphatase STEP reverses cognitive deficits in a mouse model of Alzheimer's disease. PLoS Biol 12:e1001923
Rahmouni, Souad; Delacroix, Laurence; Liu, Wallace H et al. (2013) Evaluating effects of tyrosine phosphatase inhibitors on T cell receptor signaling. Methods Mol Biol 1053:241-70
Tautz, Lutz; Sergienko, Eduard A (2013) High-throughput screening for protein tyrosine phosphatase activity modulators. Methods Mol Biol 1053:223-40
Tautz, Lutz; Critton, David A; Grotegut, Stefan (2013) Protein tyrosine phosphatases: structure, function, and implication in human disease. Methods Mol Biol 1053:179-221