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The schizophrenia susceptibility gene NAGA regulates dendritic spine density: further evidence for the dendritic spine pathology of schizophrenia

Molecular Psychiatry volume 26, pages 7102–7104 (2021)Cite this article

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The pathophysiology of schizophrenia remains largely unknown so far. However, lines of evidence suggest that dendritic spine deficits (dendritic spine pathology) play a pivotal role in schizophrenia [1,2,3]. Both genetic and morphological studies support dendritic spine pathology in schizophrenia. For example, recent studies have demonstrated the pivotal role of the schizophrenia risk gene C4A (which is located in the MHC, a region with genetic variants showing the most significant associations with schizophrenia [4]) in synapse elimination and refinement [5, 6]. In addition, morphological studies also showed deficits of dendritic spines in schizophrenia [3, 7]. These studies suggested the important role of dendritic spine pathology in schizophrenia. Nevertheless, the genetic and molecular basis of dendritic spine pathology in schizophrenia remains largely unknown.

We recently showed that the functional schizophrenia risk variant rs1801311 might contribute to disease susceptibility by regulating NAGA [8], a gene encodes the α-N-acetylgalactosaminase and is mainly involved in the regulation of glycoproteins and glycolipids metabolism. Of note, rs1801311 showed the most significant association with NAGA expression in brains (the dorsolateral prefrontal cortex) of schizophrenia cases (expression quantitative trait loci data were from the Common Mind Consortium (CMC), N = 258 cases) [9] (Supplementary Fig. S1). We have showed the important role of Naga in regulating proliferation and differentiation of neural stem cells. Transcriptome analysis also revealed that Naga regulates pathways related to synapse organization and neurotransmitter transport [8], suggesting that NAGA may also have a role in regulating morphogenesis of dendritic spines.

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Fig. 1: Naga knockdown resulted in significant decrease of dendritic spine density.

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Acknowledgements

This study was equally supported by the Key Research Project of Yunnan Province (202101AS070055) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17). Also was supported by the Distinguished Young Scientists grant of the Yunnan Province (202001AV070006), the Innovative Research Team of Science and Technology department of Yunnan Province (2019HC004), the Western Light Innovative Research Team of Chinses Academy of Sciences, the National Nature Science Foundation of China (31900414 to Y.X.H, 31970561 to X.J.L) and Henan Provincial Key Laboratory of Biological Psychiatry Open Project (ZDSYS2020002 to S.W.L). We thank Miss. Qian Li for her technical assistance.

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  1. These authors contributed equally: Yifan Li, Shiwu Li

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Yifan Li, Shiwu Li, Jiewei Liu, Yongxia Huo & Xiong-Jian Luo

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Yifan Li & Xiong-Jian Luo

  3. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China

    Xiong-Jian Luo

  4. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Xiong-Jian Luo

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  1. Yifan Li
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Contributions

XJL conceived, designed and supervised the whole study. YFL and SWL isolated the primary rat neurons, cultured the neurons and conducted the morphological analyses (dendritic spine density of neurons). JWL performed the data analysis. YXH contributed to this work in data interpretation, data analysis and manuscript revision. YFL wrote the draft of the manuscript. XJL oversaw the project and finalized the manuscript. All authors revised the manuscript critically and approved the final version.

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Correspondence to Xiong-Jian Luo.

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Li, Y., Li, S., Liu, J. et al. The schizophrenia susceptibility gene NAGA regulates dendritic spine density: further evidence for the dendritic spine pathology of schizophrenia. Mol Psychiatry 26, 7102–7104 (2021). https://doi.org/10.1038/s41380-021-01261-4

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