Current Concepts of the Role of the STEP Striatal-Enriched Protein Tyrosine Phosphatase in the Pathological and Neurodegenerative Processes in the Brain

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Abstract

Striatal-enriched protein tyrosine phosphatase (STEP) is an intracellular protein involved in key signaling cascades of the nerve cell. By regulating the membrane localization of glutamate receptors and the activity of several signaling kinases, STEP can influence processes of neuroplasticity and synaptic function, and participate in the regulation of behavior, cognitition, and memory. STEP can act as an intermediary between the brain’s neurotrophic, dopaminergic, and glutamatergic systems. Dysregulation of STEP expression and function is observed in several neurodegenerative and psychiatric disorders, as well as in aging and traumatic brain injuries. In Alzheimer’s and Parkinson’s diseases, as well as in fragile X syndrome, there is an increase in STEP activity and expression in the brains of patients and in animal models of these diseases. There is evidence of this phosphatase’s involvement in the mechanisms of depression, autism spectrum disorders, schizophrenia, and anxiety; however, different model systems and experimental conditions yield contradictory results. STEP plays a modulatory role in the nervous system’s response to traumatic brain injuries, ischemic stroke, epileptic seizures, and stress exposure. Due to STEP’s involvement in the pathogenesis of numerous nervous system disorders, this phosphatase has been actively studied over the past decade. In this review, we comprehensively examine the existing data on the role of STEP phosphatase in the functioning of CNS and in the mechanisms of disease development and the response of nerve cells to damaging influences.

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About the authors

V. S. Moskalyuk

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: v.moskaliuk@alumni.nsu.ru
Russian Federation, Novosibirsk

A. V. Kulikov

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: v.moskaliuk@alumni.nsu.ru
Russian Federation, Novosibirsk

V. S. Naumenko

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: v.moskaliuk@alumni.nsu.ru
Russian Federation, Novosibirsk

E. A. Kulikova

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: v.moskaliuk@alumni.nsu.ru
Russian Federation, Novosibirsk

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2. Fig. 1. Regulation mechanisms and substrates of STEP. STEP dephosphorylates the GluN2B and GluA2 subunits of NMDA and AMPA receptors, respectively, which entails their inactivation and internalisation. Dephosphorylation of Fyn, Pyk2, ERK1/2 and p38 kinases results in inhibition of their activity and deactivation of downstream signalling pathways. Dephosphorylation of SPIN90 causes the release of cofilin, which depolymerises actin. STEP is activated by dephosphorylation, which is regulated by the PP2B/DARPP-32/PP1 cascade. The reverse process is catalysed by protein kinase A (PKA). STEP is degraded by the ubiquitin-proteasome system or cleaved by the protease calpain to form an inactive STEP33 isoform, which can bind to other STEP isoforms and thereby deactivate them. Activation of the BDNF receptor TrkB leads to degradation of STEP through the ubiquitin-proteasome system

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3. Fig. 2. Mechanisms of STEP involvement in neurodegenerative processes. In Alzheimer's disease, amyloid beta (Aβ) disrupts the ubiquitin-proteasome system and can also activate α7 nicotinic acetylcholine receptors, which leads to intracellular calcium current, activation of PP2B/DARPP-32/PP1 phosphatase signalling cascade, which regulates STEP activity. Deactivation of STEP substrates ERK kinase and glutamate receptors NMDA and AMPA leads to the development of neurodegenerative processes. Parkinson's disease is characterised by abnormalities in the E3 ligase PARKIN, which leads to STEP accumulation. In fragile X chromosome syndrome, the absence of FMRP protein, which normally binds mRNA of the Ptpn5 gene, causes an increased level of local STEP translation. In Huntington's disease there is a decrease in STEP levels due to malfunction of mutant hantingtin protein (HTT) and/or compensatory processes, which has neuroprotective effects. In aging there is also an increased level of STEP, which is associated with dysfunction of the ubiquitin-proteasome system

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4. Fig. 3. STEP in mental disorders. For the cited psychiatric disorders, there are mixed data regarding STEP involvement. Changes in STEP expression depend on the study model and brain structure. 1The Ptpn5 gene knockout did not affect anxiety behaviour in wild-type mice, but increased anxiety in Fmr1 gene knockout mice. 2The Ptpn5 gene knockout had a positive effect on symptoms induced by PCP administration, but also caused deficits in prepulse inhibition, a characteristic cognitive symptom of schizophrenia

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5. Fig. 4. Neuroprotective and modulating role of STEP. In local ischaemia, there is a decrease in the mRNA level of Ptpn5 gene and an increase in the level of inactive STEP33 isoform. In global ischaemia, neuronal survival depends on the mRNA level of the Ptpn5 gene. During brain injury in mice, there is an increase in STEP61 levels in the brain and a decrease in phosphorylation and expression of glutamate NMDA receptors. In cell cultures, sublethal exposure results in increased STEP61 levels, and lethal exposure is accompanied by decreased STEP phosphorylation and increased STEP33 levels. Stress tolerance in rats is positively correlated (∝) with STEP61 protein levels in the brain, and chronic stress leads to decreased mRNA levels of the Ptpn5 gene and increased NMDA receptor expression at the synaptic membrane. Neuronal survival during epileptic seizures is negatively correlated with the level of Ptpn5 gene expression. Knockout of this gene or inhibition of STEP by TS-2153 increases the resistance of mice to epileptic seizures

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