Abstract
Striatal-enriched protein tyrosine phosphatase (STEP) is a CNS-enriched protein implicated in multiple neurologic and neuropsychiatric disorders. STEP regulates key signaling proteins required for synaptic strengthening as well as NMDA and AMPA receptor trafficking. Both high and low levels of STEP disrupt synaptic function and contribute to learning and behavioral deficits. High levels of STEP are present in human postmortem samples and animal models of Alzheimer's disease, Parkinson's disease, and schizophrenia and in animal models of fragile X syndrome. Low levels of STEP activity are present in additional disorders that include ischemia, Huntington's chorea, alcohol abuse, and stress disorders. Thus the current model of STEP is that optimal levels are required for optimal synaptic function. Here we focus on the role of STEP in Alzheimer's disease and the mechanisms by which STEP activity is increased in this illness. Both genetic lowering of STEP levels and pharmacological inhibition of STEP activity in mouse models of Alzheimer's disease reverse the biochemical and cognitive abnormalities that are present. These findings suggest that STEP is an important point for modulation of proteins required for synaptic plasticity.
Highlights
There are 107 protein tyrosine phosphatases (PTPs) in the human genome and many of these play important roles in cellular function [1]
To confirm that Aβ binding to α7nAChRs and activation of phosphatase 1 (PP1) were leading to activation of Striatal-enriched protein tyrosine phosphatase (STEP), neuronal cultures derived from α7nAChR KO mice and treated with Aβ were used to test whether activation of STEP was prevented in the absence of α7nAChRs
STEP acts by dephosphorylating regulatory tyrosine residues in substrates that include subunits of both NMDA and AMPA glutamate receptors, thereby leading to internalization of these receptor complexes
Summary
There are 107 protein tyrosine phosphatases (PTPs) in the human genome and many of these play important roles in cellular function [1]. Striatal-enriched protein tyrosine phosphatase (STEP), encoded by the PTPN5 gene, is a CNS-enriched member of the PTP family [2]. STEP is an intracellular PTP, expressed throughout the CNS with the exception of the cerebellum [4]. Increased expression of STEP disrupts synaptic function and is associated with a number of neuropsychiatric disorders, such as Alzheimer’s disease [14,15,16,17]. Pharmacological inhibition of STEP would be predicted to alleviate synaptic dysfunction in Alzheimer’s disease, and the successful effort in this area is reviewed below
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