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Inhibition of STEP 61 ameliorates deficits in mouse and hiPSC-based schizophrenia models

Xu, J ; Hartley, B J ; Kurup, P ; Phillips, A ; Topol, A ; Xu, M ; Ononenyi, C ; Foscue, E ; Ho, S-M ; Baguley, T D ; Carty, N ; Barros, C S ; Müller, U ; Gupta, S ; Gochman, P ; Rapoport, J ; Ellman, J A ; Pittenger, C ; Aronow, B ; Nairn, A C ; Nestor, M W ; Lombroso, P J ; Brennand, K J

Molecular psychiatry, 2018-02, Vol.23 (2), p.271 [Periódico revisado por pares]

England

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Título:
Inhibition of STEP 61 ameliorates deficits in mouse and hiPSC-based schizophrenia models
Autor: Xu, J ; Hartley, B J ; Kurup, P ; Phillips, A ; Topol, A ; Xu, M ; Ononenyi, C ; Foscue, E ; Ho, S-M ; Baguley, T D ; Carty, N ; Barros, C S ; Müller, U ; Gupta, S ; Gochman, P ; Rapoport, J ; Ellman, J A ; Pittenger, C ; Aronow, B ; Nairn, A C ; Nestor, M W ; Lombroso, P J ; Brennand, K J
Assuntos: Animals ; Disease Models, Animal ; Female ; Humans ; Induced Pluripotent Stem Cells - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neuregulin-1 - genetics ; Neurons - metabolism ; Phosphorylation ; Protein Tyrosine Phosphatases - genetics ; Protein Tyrosine Phosphatases - physiology ; Rats ; Receptors, N-Methyl-D-Aspartate - metabolism ; Schizophrenia - genetics ; Schizophrenia - metabolism ; Ubiquitination
É parte de: Molecular psychiatry, 2018-02, Vol.23 (2), p.271
Descrição: 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 is elevated in the cortex in the Nrg1 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 mice. STEP 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 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP dysfunction in SZ.
Editor: England
Idioma: Inglês

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Inhibition of STEP 61 ameliorates deficits in mouse and hiPSC-based schizophrenia models

Xu, J ; Hartley, B J ; Kurup, P ; Phillips, A ; Topol, A ; Xu, M ; Ononenyi, C ; Foscue, E ; Ho, S-M ; Baguley, T D ; Carty, N ; Barros, C S ; Müller, U ; Gupta, S ; Gochman, P ; Rapoport, J ; Ellman, J A ; Pittenger, C ; Aronow, B ; Nairn, A C ; Nestor, M W ; Lombroso, P J ; Brennand, K J

England

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