The DISC1 Ser704Cys substitution affects centrosomal localization of its binding partner PCM1 in glia in human brain
The DISC1 Ser704Cys substitution affects centrosomal localization of its binding partner PCM1 in glia in human brain
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DOI：
10.1093/hmg/ddq130
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发表时间：
2010-06-15
影响因子：
3.5
通讯作者：
Harrison, Paul J.
中科院分区：
文献类型：
--
作者：
Eastwood, Sharon L.;Walker, Mary;Harrison, Paul J.
精神分裂症中断 1 (DISCI) 与精神分裂症以及包括灰质体积和工作记忆表现在内的大脑表型具有遗传相关性。然而，这些关联的分子和细胞基础仍有待阐明。一种潜在的机制可能是通过改变 DISCI 与其结合伙伴的相互作用。在这种情况下，我们之前证明了一种 DISCI 变体 Leu607Phe 影响 SH-SY5Y 细胞中中心粒周围物质 1 (PCM1) 的中心体定位程度。目前的研究将这项工作扩展到人类大脑，并包括另一个 DISC1 编码变体 Ser704Cys。使用免疫组织化学，我们首先表征了 PCM1 在人类颞上回 (STG) 中的分布。 PCM1 免疫反应性位于神经胶质细胞的中心体，但不在神经元中，显示出广泛的免疫反应性。我们对 81 名对照者和 67 名精神分裂症受试者的 STG 神经胶质细胞中的中心体 PCM1 免疫反应性进行了定量，并进行了两种多态性的基因分型。 Cys704 携带者的中心体 PCM1 免疫反应区域小于 Ser704 纯合子，Phe607 纯合子的趋势与 Leu607 携带者相似，在 SH-SY5Y 细胞中复制了这一发现。对照组和精神分裂症患者之间没有发现差异。这些发现在体内证实了 DISC1 编码变体调节中心体 PCM1 定位，突出了 DISCI 在神经胶质功能中的作用，并提供了一种可能的细胞机制，有助于这些 DISC1 变体与精神表型的关联。 DISCI 基因型的这种影响是否延伸到其他中心体蛋白和 DISC1 结合伴侣仍有待确定。
Disrupted-in-schizophrenia 1 (DISCI) has been genetically associated with schizophrenia, and with brain phenotypes including grey matter volume and working memory performance. However, the molecular and cellular basis for these associations remains to be elucidated. One potential mechanism may be via an altered interaction of DISCI with its binding partners. In this context, we previously demonstrated that one DISCI variant, Leu607Phe, influenced the extent of centrosomal localization of pericentriolar material 1 (PCM1) in SH-SY5Y cells. The current study extends this work to human brain, and includes another DISC1 coding variant, Ser704Cys. Using immunohistochemistry, we first characterized the distribution of PCM1 in human superior temporal gyrus (STG). PCM1 immunoreactivity was localized to the centrosome in glia, but not in neurons, which showed widespread immunoreactivity. We quantified centrosomal PCM1 immunoreactivity in STG glia of 81 controls and 67 subjects with schizophrenia, genotyped for the two polymorphisms. Centrosomal PCM1 immunoreactive area was smaller in Cys704 carriers than in Ser704 homozygotes, with a similar trend in Phe607 homozygotes compared with Leu607 carriers, replicating the finding in SH-SY5Y cells. No differences were seen between controls and subjects with schizophrenia. These findings confirm in vivo that DISC1 coding variants modulate centrosomal PCM1 localization, highlight a role for DISCI in glial function and provide a possible cellular mechanism contributing to the association of these DISC1 variants with psychiatric phenotypes. Whether this influence of DISCI genotype extends to other centrosomal proteins and DISC1 binding partners remains to be determined.