ABSTRACT
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 STEP61 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. STEP61 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 STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.
Subject(s)
Protein Tyrosine Phosphatases/physiology , Schizophrenia/metabolism , 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 , Rats , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/genetics , UbiquitinationABSTRACT
The genetic and epigenetic factors contributing to risk for schizophrenia (SZ) remain unresolved. Here we demonstrate, for the first time, perturbed global protein translation in human-induced pluripotent stem cell (hiPSC)-derived forebrain neural progenitor cells (NPCs) from four SZ patients relative to six unaffected controls. We report increased total protein levels and protein synthesis, together with two independent sets of quantitative mass spectrometry evidence indicating markedly increased levels of ribosomal and translation initiation and elongation factor proteins, in SZ hiPSC NPCs. We posit that perturbed levels of global protein synthesis in SZ hiPSC NPCs represent a novel post-transcriptional mechanism that might contribute to disease progression.
Subject(s)
Induced Pluripotent Stem Cells/metabolism , Neural Stem Cells/metabolism , Neurons/metabolism , Prosencephalon/metabolism , Schizophrenia/metabolism , Cell Differentiation , Cells, Cultured , HumansSubject(s)
Cell Differentiation/physiology , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Induced Pluripotent Stem Cells/physiology , Schizophrenia/pathology , Female , Humans , Induced Pluripotent Stem Cells/pathology , Male , Tubulin/metabolism , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Primary extra-nasopharyngeal sites of angiofibromas are extremely unusual. We describe a rare case of extra-nasopharyngeal angiofibroma in a one year old child arising from the left maxilla and indirectly involving the lacrimal system. The initial presentation was of a swelling in the region of the left medial canthus. Only four cases of extra-nasopharyngeal angiofibromas in children below the age of two have been described. We review the literature on what is known about extra-nasopharyngeal angiofibromas.
