Abstract
This commentary focuses on potential molecular mechanisms related to the dysfunctional synaptic plasticity that is associated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Specifically, we focus on the role of striatal-enriched protein tyrosine phosphatase (STEP) in modulating synaptic function in these illnesses. STEP affects neuronal communication by opposing synaptic strengthening and does so by dephosphorylating several key substrates known to control synaptic signaling and plasticity. STEP levels are elevated in brains from patients with Alzheimer’s and Parkinson’s disease. Studies in model systems have found that high levels of STEP result in internalization of glutamate receptors as well as inactivation of ERK1/2, Fyn, Pyk2, and other STEP substrates necessary for the development of synaptic strengthening. We discuss the search for inhibitors of STEP activity that may offer potential treatments for neurocognitive disorders that are characterized by increased STEP activity. Future studies are needed to examine the mechanisms of differential and region-specific changes in STEP expression pattern, as such knowledge could lead to targeted therapies for disorders involving disrupted STEP activity.
Highlights
Protein tyrosine phosphorylation is regulated by the fine balance of the activity of protein tyrosine kinases and protein tyrosine phosphatases (PTPs) and plays a critical role in many cellular activities, including gene regulation, cell growth, differentiation, migration, and synaptic plasticity[1]
Dysregulation or mutations in genes that encode PTPs lead to metabolic, neurological, developmental, and psychiatric disorders[1,4,5,6]
These important advances have motivated efforts to find PTP inhibitors that are effective against diabetes, cancer, neurodegeneration, and other serious disorders[7,8]
Summary
Protein tyrosine phosphorylation is regulated by the fine balance of the activity of protein tyrosine kinases and protein tyrosine phosphatases (PTPs) and plays a critical role in many cellular activities, including gene regulation, cell growth, differentiation, migration, and synaptic plasticity[1]. Mass spectrometry confirmed modifications to the active site cysteine, suggesting that a sulfur from the benzopentathiepin ring is retained These findings support recent research showing that oxidative regulation of PTPs is an important regulatory mechanism occurring in cells to link tyrosine phosphorylation signaling and redox status[68,69]. A recent study showed that decreased STEP activity in the mouse striatum (through protein kinase A [PKA] phosphorylation of STEP) is important for improving motor learning[82] These findings are consistent with earlier studies showing that STEP knockout mice have facilitated hippocampal and amygdala learning but extend the possible involvement of STEP to other types of learning. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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