Neuronal serine racemase associates with Disrupted-In-Schizophrenia-1 and DISC1 agglomerates: Implications for schizophrenia.
Neuronal serine racemase associates with Disrupted-In-Schizophrenia-1 and DISC1 agglomerates: Implications for schizophrenia.
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DOI：
10.1016/j.neulet.2018.10.055
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发表时间：
2019-01-23
影响因子：
2.5
通讯作者：
Lin H
中科院分区：
文献类型：
--
作者：
Jacobi AA;Halawani S;Lynch DR;Lin H
d-丝氨酸是甘氨酸结合位点n -甲基-d-天冬氨酸受体（NMDARs）的内源性凝血剂，由丝氨酸消旋酶（SR）转化l-丝氨酸合成。SR/ d-丝氨酸和分裂- in -1 （DISC1）的失调有助于精神分裂症在会聚通路上的发病机制，因为星形胶质细胞中SR-DISC1结合的扰动会引发小鼠的精神分裂症样行为。然而，神经元SR与DISC1之间的关联仍然难以捉摸。在这里，我们报道SR与皮质神经元中的DISC1及其聚集相关，这可以通过NMDAR活性来调节。内源性SR与DISC1共定位，DISC1在体细胞中有大的聚集，在皮质神经元的核和树突中有较小的点。共免疫沉淀实验表明SR与皮质神经元裂解物中的DISC1相互作用，表明神经元中存在功能性SR-DISC1复合物。此外，外源d -丝氨酸的应用显著增加了SR与DISC1的相互作用，DISC1-SR大团聚体的数量和在trn不溶性颗粒部分中随SR聚集的DISC1聚集形式的水平，而甘氨酸与甘氨酸转运蛋白抑制剂的应用未能增加它们的相互作用，DISC1-SR大团聚体的丰度和DISC1聚集形式的水平。7-氯代尿酸是NMDARs甘氨酸位点的一种特异性拮抗剂，可阻断d -丝氨酸的增加，提示通过NMDARs介导。因此，我们的研究结果证明了神经元SR与DISC1及其凝聚体的关联，这可以通过d -丝氨酸调节，从而验证了一种新的神经元SR-DISC1复合物对NMDAR激活的反应，并提供了一种与精神分裂症相关的通路聚集的分子机制。
D-serine, an endogenous coagonist of N-methyl-d-aspartate receptors (NMDARs) at the glycine binding site, is synthesized by serine racemase (SR) through conversion of L-serine. Dysregulation of SR/D-serine and Disrupted-In-Schizophrenia-1 (DISC1) contributes to the pathogenesis of schizophrenia at converging pathways, as perturbation of SR-DISC1 binding in astrocytes elicits schizophrenia-like behaviors in mice. However, an association of neuronal SR with DISC1 remains elusive. Here we report that SR associates with DISC1 and its agglomerates in cortical neurons, which can be modulated by NMDAR activity. Endogenous SR colocalizes with DISC1 large agglomerates in the soma and with smaller puncta in the nucleus and dendrites of cortical neurons. Co-immunoprecipitation assays demonstrate SR interaction with DISC1 in cortical neuronal lysates, suggesting the physiological presence of functional SR-DISC1 complexes in neurons. Moreover, exogenous D-serine application significantly increases the interaction of SR with DISC1, the number of DISC1-SR large agglomerates and the levels of DISC1 agglomerated form along with SR in the triton-insoluble pellet fraction, whereas application of glycine with a glycine transporter inhibitor fails to increase their interactions, abundance of DISC1-SR large agglomerates and levels of DISC1 agglomerated form. This increase by D-serine application is blocked by 7-chlorokynurenic acid, a specific antagonist at the glycine site of NMDARs, suggesting mediation through NMDARs. Our findings thus demonstrate neuronal SR association with DISC1 and its agglomerates, which can be modulated by D-serine, thereby validating a novel neuronal SR-DISC1 complex responsive to NMDAR activation and providing a molecular mechanism by which pathways implicated in schizophrenia converge.
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影响因子：
10.6
作者：
Balu DT;Presti KT;Huang CCY;Muszynski K;Radzishevsky I;Wolosker H;Guffanti G;Ressler KJ;Coyle JT
通讯作者：
Coyle JT
DOI：
10.1111/j.1601-183x.2010.00656.x
发表时间：
2011-03
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
DeVito LM;Balu DT;Kanter BR;Lykken C;Basu AC;Coyle JT;Eichenbaum H
通讯作者：
Eichenbaum H
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
影响因子：
64.3
作者：
Kantrowitz, Joshua T.;Woods, Scott W.;Javitt, Daniel C.
通讯作者：
Javitt, Daniel C.
影响因子：
11
作者：
Basu, A. C.;Tsai, G. E.;Coyle, J. T.
通讯作者：
Coyle, J. T.