학술논문
Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models
Original Article
STriatal-Enriched protein tyrosine Phosphatase; and human induced pluripotent stem cell
Original Article
STriatal-Enriched protein tyrosine Phosphatase; and human induced pluripotent stem cell
Document Type
Report
Author
Source
Molecular Psychiatry. February 2018, Vol. 23 Issue 2, 271
Subject
Language
English
ISSN
1359-4184
Abstract
Author(s): J Xu [1]; B J Hartley [2, 3]; P Kurup [1]; A Phillips [4]; A Topol [2, 3]; M Xu [5]; C Ononenyi [1]; E Foscue [1]; S-M Ho [...]
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP[sub.61] is elevated in the cortex in the Nrg1[sup.+/-] knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1[sup.+/-] mice. STEP[sub.61] protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP[sub.61] protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP[sub.61] dysfunction in SZ. Molecular Psychiatry (2018) 23, 271-281; doi: 10.1038/mp.2016.163; published online 18 October 2016
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP[sub.61] is elevated in the cortex in the Nrg1[sup.+/-] knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1[sup.+/-] mice. STEP[sub.61] protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP[sub.61] protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP[sub.61] dysfunction in SZ. Molecular Psychiatry (2018) 23, 271-281; doi: 10.1038/mp.2016.163; published online 18 October 2016