The long-term goal of this research is to determine the role of tyrosine phosphatases and dual-specificity phosphatases in neurological disorders of the basal ganglia and related structures. Our recent findings indicate that a striatal enriched tyrosine phosphatase, STEP, specifically expressed in the neurons of the cortex, hippocampus and striatum may participate in cell survival following an excitotoxic insult. The activity of STEP is itself regulated by the neurotransmitters dopamine and glutamate through phosphorylation and dephosphorylartion of a critical serine residue within the kinase interacting motif or KIM domain. Glutamate/NMDA receptor mediated influx of Ca2+ activates STEP, whereas dopamine/D1 receptor mediated PKA activation leads to inactivation of STEP. The proposed study will now test whether STEP is activated through NR2B-NMDA receptors, a pool of NMDA receptor that is associated with glutamate excitotoxicity. It will also investigate whether active STEP in turn can down regulate or inhibit multiple interrelated pathways that are involved in glutamate/NMDA receptor-mediated cell death. We anticipate that active STEP, as part of a feed-back loop, can down regulate NR2B-NMDA receptor channel activity through tyrosine dephosphorylation of NR2B subunit, thereby inhibiting Ca2+ overload and subsequent cell damage. It can also inhibit the activation of the p38 MAP kinase signaling pathway that has been attributed to cell death in multiple neurodegenerative disorders. In this way STEP may promote cell survival following an initial insult. However depending upon the severity of the insult STEP may be proteolytically cleaved and eventually degraded, thereby facilitating activation of cell death pathways. The study will further investigate if a constitutively active form of STEP that cannot be proteolytically cleaved and can be delivered in vivo will be able to attenuate ischemic brain damage, where the involvement of glutamate excitotoxicity is well established. These studies will involve neuron culture experiments of glutamate toxicity and an animal model of ischemic stroke and will utilize biochemical, immunocytochemical and molecular biology techniques. The findings will help us to determine whether the tyrosine phosphatase STEP may be therapeutically beneficial and can be considered for the treatment of ischemic stroke and related neurological disorders. Project Narrative The goal of the proposed study is to understand the role of a brain-enriched and neuron-specific tyrosine phosphatase, STEP, in neuronal cell death following an excitotoxic insult. The findings will help us to determine whether STEP can attenuate excitotoxic neuronal cell death and can be considered as a potential therapeutic target for the treatment of ischemic stroke and related neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059962-05
Application #
8244483
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$321,563
Indirect Cost
$107,188
Name
University of New Mexico
Department
Neurology
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Rajagopal, Sathyanarayanan; Deb, Ishani; Poddar, Ranjana et al. (2016) Aging is associated with dimerization and inactivation of the brain-enriched tyrosine phosphatase STEP. Neurobiol Aging 41:25-38
Poddar, Ranjana; Rajagopal, Sathyanarayanan; Shuttleworth, C William et al. (2016) Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP: MOLECULAR BASIS FOR ZN2+-INDUCED ERK MAPK ACTIVATION. J Biol Chem 291:813-25
Deb, Ishani; Manhas, Namratta; Poddar, Ranjana et al. (2013) Neuroprotective role of a brain-enriched tyrosine phosphatase, STEP, in focal cerebral ischemia. J Neurosci 33:17814-26
Poddar, Ranjana; Paul, Surojit (2013) Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death. J Neurochem 124:558-70
Deb, Ishani; Poddar, Ranjana; Paul, Surojit (2011) Oxidative stress-induced oligomerization inhibits the activity of the non-receptor tyrosine phosphatase STEP61. J Neurochem 116:1097-111
Mukherjee, Saibal; Poddar, Ranjana; Deb, Ishani et al. (2011) Dephosphorylation of specific sites in the kinase-specificity sequence domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP. Biochem J 440:115-25
Poddar, Ranjana; Deb, Ishani; Mukherjee, Saibal et al. (2010) NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death. J Neurochem 115:1350-62
Paul, Surojit; Connor, John A (2010) NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling. J Neurochem 114:1107-18