Impaired Autophagy in Hilar Mossy Cells of the Dentate Gyrus and Its Implication in Schizophrenia

Yefeng Yuan^{a, b},
Hao Wang^a,
Zongbo Wei^{a, b},
Wei Li^{a, c
, ,}

a.
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
b.
University of Chinese Academy of Sciences, Beijing 100039, China
c.
Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100053, China

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Corresponding author: E-mail address: wli@genetics.ac.cn (Wei Li)

摘要

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Abstract: Schizophrenia (SCZ) is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 (dystrobrevin-binding protein 1) gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-1C isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyrus, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-1-deficient sandy (sdy) mice (a mouse model of SCZ) is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3-II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-1C. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells ofsdy mice. In addition, overexpression of dysbindin-1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin-1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.
- Dysbindin-1 /
- Mossy cell /
- Neurodegeneration /
- Autophagy /
- Schizophrenia

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参考文献(33)

[1]	Balu, D.T., Coyle, J.T. Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia Neurosci. Biobehav. Rev., 35 (2011),pp. 848-870
[2]	Berry, D.L., Baehrecke, E.H. Cell, 131 (2007),pp. 1137-1148
[3]	Bhardwaj, S.K., Baharnoori, M., Sharif-Askari, B. et al. Behavioral characterization of dysbindin-1 deficient sandy mice Behav. Brain Res., 197 (2009),pp. 435-441
[4]	Boya, P., Gonzalez-Polo, R.A., Casares, N. et al. Inhibition of macroautophagy triggers apoptosis Mol. Cell Biol., 25 (2005),pp. 1025-1040
[5]	Chen, X.W., Feng, Y.Q., Hao, C.J. et al. J. Cell Biol., 181 (2008),pp. 791-801
[6]	Cho, D.H., Jo, Y.K., Hwang, J.J. et al. Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells Cancer Lett., 274 (2009),pp. 95-100
[7]	Fanous, A.H., Kendler, K.S. Genetics of clinical features and subtypes of schizophrenia: a review of the recent literature Curr. Psychiatry Rep., 10 (2008),pp. 164-170
[8]	Fei, E., Ma, X., Zhu, C. et al. Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression J. Biol. Chem., 285 (2010),pp. 38630-38640
[9]	Feng, Y.Q., Zhou, Z.Y., He, X. et al. Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia Schizophr. Res., 106 (2008),pp. 218-228
[10]	Hasegawa, K., Yoshikawa, K. J. Neurosci., 28 (2008),pp. 8772-8784
[11]	Hattori, S., Murotani, T., Matsuzaki, S. et al. Biochem. Biophys. Res. Commun., 373 (2008),pp. 298-302
[12]	Huang, L., Kuo, Y.M., Gitschier, J. The pallid gene encodes a novel, syntaxin 13-interacting protein involved in platelet storage pool deficiency Nat. Genet., 23 (1999),pp. 329-332
[13]	Kempermann, G., Krebs, J., Fabel, K. The contribution of failing adult hippocampal neurogenesis to psychiatric disorders Curr. Opin. Psychiatry, 21 (2008),pp. 290-295
[14]	Larimore, J., Zlatic, S.A., Gokhale, A. et al. Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes J. Biol. Chem., 289 (2014),pp. 14291-14300
[15]	Li, W., Feng, Y., Hao, C. et al. The BLOC interactomes form a network in endosomal transport J. Genet. Genomics, 34 (2007),pp. 669-682
[16]	Li, W., He, M., Zhou, H. et al. Mutational data integration in gene-oriented files of the Hermansky-Pudlak syndrome database Hum. Mutat., 27 (2006),pp. 402-407
[17]	Li, W., Zhang, Q., Oiso, N. et al. Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) Nat. Genet., 35 (2003),pp. 84-89
[18]	Ma, X., Fei, E., Fu, C. et al. Dysbindin-1, a schizophrenia-related protein, facilitates neurite outgrowth by promoting the transcriptional activity of p53 Mol. Psychiatry, 16 (2011),pp. 1105-1116
[19]	Mah, L.Y., Ryan, K.M. Autophagy and cancer Cold Spring Harb. Perspect. Biol., 4 (2012)
[20]	Meng, Y., Yong, Y., Yang, G. et al. Autophagy alleviates neurodegeneration caused by mild impairment of oxidative metabolism J. Neurochem., 126 (2013),pp. 805-818
[21]	Merenlender-Wagner, A., Malishkevich, A., Shemer, Z. et al. Autophagy has a key role in the pathophysiology of schizophrenia Mol. Psychiatry (2013)
[22]	Ming, G.L., Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions Neuron, 70 (2011),pp. 687-702
[23]	Nelson, M.P., Shacka, J.J. Autophagy modulation in disease therapy: where do we stand? Curr. Pathobiol. Rep., 1 (2013),pp. 239-245
[24]	Nixon, R.A., Yang, D.S. Autophagy and neuronal cell death in neurological disorders Cold Spring Harb. Perspect. Biol., 4 (2012)
[25]	Scott, R.C., Juhasz, G., Neufeld, T.P. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death Curr. Biol., 17 (2007),pp. 1-11
[26]	Straub, R.E., Jiang, Y., MacLean, C.J. et al. Am. J. Hum. Genet., 71 (2002),pp. 337-348
[27]	Takao, K., Toyama, K., Nakanishi, K. et al. Mol. Brain, 1 (2008),p. 11
[28]	Talbot, K., Louneva, N., Cohen, J.W. et al. Synaptic dysbindin-1 reductions in schizophrenia occur in an isoform-specific manner indicating their subsynaptic location PLoS One, 6 (2011)
[29]	Talbot, K., Ong, W.Y., Blake, D.J. et al.
[30]	Taniura, H., Matsumoto, K., Yoshikawa, K. Physical and functional interactions of neuronal growth suppressor necdin with p53 J. Biol. Chem., 274 (1999),pp. 16242-16248
[31]	Wang, H., Yuan, Y., Zhang, Z. et al. Dysbindin-1C is required for the survival of hilar mossy cells and the maturation of adult newborn neurons in dentate gyrus J. Biol. Chem., 289 (2014),pp. 29060-29072
[32]	Wei, A.H., Li, W. Hermansky-Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis Pigment Cell Melanoma Res., 26 (2013),pp. 176-192
[33]	Zhang, Q., Li, W., Novak, E.K. et al. Hum. Mol. Genet., 11 (2002),pp. 697-706