Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice

Kröcher, Tim; Malinovskaja, Kristina; Jürgenson, Monika; Aonurm-Helm, Anu; Zharkovskaya, Tamara; Kalda, Anti; Röckle, Iris; Schiff, Miriam; Weinhold, Birgit; Gerardy‐Schahn, Rita; Hildebrandt, Herbert; Zharkovsky, Alexander

doi:10.1007/s00429-013-0638-z

Cited by 44 publications

(42 citation statements)

References 70 publications

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“…Animal studies also support the association between ST8SIA2 and schizophrenia. St8sia2 −/− mice exhibited schizophrenia‐like behavior (Calandreau et al, ; Kröcher et al, ), enlarged lateral ventricles, decreased thalamic volume, and thalamocortical disconnectivity (Kröcher et al, ), reminiscent of the anomalies in schizophrenia (Mitelman et al, ; Wobrock et al, ; Woodward et al, ).…”

Section: Introductionmentioning

confidence: 99%

ST8SIA2 promotes oligodendrocyte differentiation and the integrity of myelin and axons

Szewczyk

Brożko

Nagalski

et al. 2016

Glia

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ST8SIA2 is a polysialyltransferase that attaches polysialic acid to the glycoproteins NCAM1 and CADM1. Polysialylation is involved in brain development and plasticity. ST8SIA2 is a schizophrenia candidate gene, and St8sia2 −/− mice exhibit schizophrenia‐like behavior. We sought to identify new pathological consequences of ST8SIA2 deficiency. Our proteomic analysis suggested myelin impairment in St8sia2 −/− mice. Histological and immune staining together with Western blot revealed that the onset of myelination was not delayed in St8sia2 −/− mice, but the content of myelin was lower. Ultrastructure analysis of the corpus callosum showed thinner myelin sheaths, smaller and irregularly shaped axons, and white matter lesions in adult St8sia2 −/− mice. Then we evaluated oligodendrocyte differentiation in vivo and in vitro. Fewer OLIG2+ cells in the cortex and corpus callosum, together with the higher percentage of undifferentiated oligodenroglia in St8sia2 −/− mice suggested an impairment in oligodendrocyte generation. Experiment on primary cultures of oligodendrocyte precursor cells (OPCs) confirmed a cell‐autonomous effect of ST8SIA2 in oligodendroglia, and demonstrated that OPC to oligodendrocyte transition is inhibited in St8sia2 −/− mice. Concluding, ST8SIA2‐mediated polysialylation influences on oligodendrocyte differentiation, and oligodendrocyte deficits in St8sia2 mice are a possible cause of the demyelination and degeneration of axons, resembling nerve fiber alterations in schizophrenia. GLIA 2016;65:34–49

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Section: Introductionmentioning

confidence: 99%

ST8SIA2 promotes oligodendrocyte differentiation and the integrity of myelin and axons

Szewczyk

Brożko

Nagalski

et al. 2016

Glia

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“…Importantly, because of differences in acceptor substrate specificity and gene expression patterns of these related enzymes, cells and tissues display unique sialoside structures, which can have important functional consequences (13)(14)(15). Studies examining sialyltransferase-deficient mice, for instance, have shed light on some of the important biological roles played by sialosides in the immune response (16 -22), brain (23)(24)(25)(26)(27), and blood/liver (19,28).…”

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confidence: 99%

Systemic Blockade of Sialylation in Mice with a Global Inhibitor of Sialyltransferases

Macauley

Arlian

Rillahan

et al. 2014

Journal of Biological Chemistry

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Background:In vivo pharmacological inhibition of sialyltransferases has, to date, not been possible. Results: 3F-NeuAc acts as a global sialyltransferase inhibitor in mice and causes kidney and liver dysfunction. Conclusion: Sialoside expression can be modulated in vivo with a sialyltransferase inhibitor. Significance: Pharmacological blockade of sialoside expression will be an important tool for future exploration of sialic acid in health and disease.

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“…Indeed, there have been several reports on the abnormal expression of polySia in diseases such as schizophrenia [10,11] and various cancers [2]. In particular, the polySia biosynthesizing enzyme, ST8SIA2 (STX, siat8b), has been reported to have some association with schizophrenia [8,12,13], bipolar disorder [14], and small cell lung cancer [15]. …”

Section: Introductionmentioning

confidence: 99%

“…In addition, ST8Sia2-KO mice showed enlarged lateral ventricles and reduction of the thalamus. ST8Sia2-KO mice displayed impaired working memory and deficits in prepulse inhibition, anhedonic behavior and increased sensitivity to amphetamine-induced hyperlocomotion that are the characteristic phenotypes observed from SZ patients [13]. Therefore, ST8Sia2-KO mice are reported to be able to use as a model animal for analyzing SZ [13].…”

Section: Introductionmentioning

confidence: 99%

“…ST8Sia2-KO mice displayed impaired working memory and deficits in prepulse inhibition, anhedonic behavior and increased sensitivity to amphetamine-induced hyperlocomotion that are the characteristic phenotypes observed from SZ patients [13]. Therefore, ST8Sia2-KO mice are reported to be able to use as a model animal for analyzing SZ [13]. On the other hand, ST8Sia4-KO mice showed different phenotypes than those of ST8Sia2, abnormal LTP and LTD in CA1, and normal mossy fiber projection in hippocampus [27].…”

Section: Introductionmentioning

confidence: 99%

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Chlorpromazine Increases the Expression of Polysialic Acid (PolySia) in Human Neuroblastoma Cells and Mouse Prefrontal Cortex

Abe

Nishimura

Mori

et al. 2017

IJMS

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The neural cell adhesion molecule (NCAM) is modified by polysialic acid (polySia or PSA) in embryonic brains. In adult brains, polySia modification of NCAM is only observed in restricted areas where neural plasticity, remodeling of neural connections, or neural generation is ongoing although the amount of NCAM remains unchanged. Impairments of the polySia-expression and several single nucleotide polymorphisms (SNPs) of the polysialyltransferase (polyST) ST8SIA2 gene are reported to be associated with schizophrenia and bipolar disorder. Chlorpromazine (CPZ) is well-known as an agent for treating schizophrenia, and our hypothesis is that CPZ may affect the polySia expression or the gene expression of polySTs or NCAM. To test this hypothesis, we analyzed the effects of CPZ on the expression of polySia-NCAM on human neuroblastoma cell line, IMR-32 cells, by immunochemical and chemical methods. Interestingly, the cell surface expression of polySia, especially those with lower chain lengths, was significantly increased on the CPZ-treated cells, while mRNAs for polySTs and NCAM, and the amounts of total polySia-NCAM remained unchanged. The addition of brefeldin A, an inhibitor of endocytosis, suppressed the CPZ-induced cell surface polySia expression. In addition, polySia-NCAM was also observed in the vesicle compartment inside the cell. All these data suggest that the level of cell surface expression of polySia in IMR-32 is highly regulated and that CPZ changes the rate of the recycling of polySia-NCAM, leading to the up-regulation of polySia-NCAM on the cell surface. We also analyzed the effect of CPZ on polySia-expression in various brain regions in adult mice and found that CPZ only influenced the total amounts of polySia-NCAM in prefrontal cortex. These results suggest a brain-region-specific effect of CPZ on the expression of total polySia in mouse brain. Collectively, anti-schizophrenia agent CPZ consistently up-regulates the expression polySia at both cellular and animal levels.

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Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice

Cited by 44 publications

References 70 publications

ST8SIA2 promotes oligodendrocyte differentiation and the integrity of myelin and axons

ST8SIA2 promotes oligodendrocyte differentiation and the integrity of myelin and axons

Systemic Blockade of Sialylation in Mice with a Global Inhibitor of Sialyltransferases

Chlorpromazine Increases the Expression of Polysialic Acid (PolySia) in Human Neuroblastoma Cells and Mouse Prefrontal Cortex

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