A DISC1 point mutation promotes oligomerization and impairs information processing in a mouse model of schizophrenia
A DISC1 point mutation promotes oligomerization and impairs information processing in a mouse model of schizophrenia
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DOI：
10.1093/jb/mvy116
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发表时间：
2019-04-01
影响因子：
2.7
通讯作者：
Kuwata, Kazuo
中科院分区：
文献类型：
--
作者：
Kakuda, Kyosuke;Niwa, Ayumi;Kuwata, Kazuo
精神分裂症中断1（DISC1）与精神分裂症密切相关，但DISC1分子间相互作用的改变如何影响大脑的信息处理仍然难以捉摸。我们发现，DISC1 点突变改变了分子间的内聚力，促进了相分离，并扰乱了精神分裂症小鼠模型中通过前脉冲抑制监测的感觉运动门控。尽管人中带有精神分裂症相关突变L607F的DISC1部分肽或小鼠中相应的L604F的DISC1部分肽的构象与野生型（WT）基本上没有区别，只要通过荧光、圆二色性、超速离心、动态光散射和核磁共振监测，原子力显微镜就能够检测到它们的形态学差异。 WT肽是圆形的并且分散良好，而突变体是不均匀的并且被破坏形成二聚体到三聚体，其沿着一个方向对齐而没有明显的聚集体形成。与野生型相比，通过 CRISPR 产生的纯合 L604F 突变小鼠在海马区的免疫组织病理学中表现出 DISC1 水平显着降低。与野生型小鼠相比，纯合突变小鼠的前脉冲抑制率显着受损。由异常分子间相互作用引起的 DISC1 分布或功能改变可能有助于精神分裂症的信息处理特征。
Disrupted-in-schizophrenia 1 (DISC1) is strongly associated with schizophrenia, but it remains elusive how the modification of the intermolecular interaction of DISC1 affects the information processing in brain. We show that a DISC1 point mutation alters intermolecular cohesiveness promoting the phase separation, and disrupts sensorimotor gating monitored by the prepulse inhibition in a mouse model of schizophrenia. Although the conformation of DISC1 partial peptide with the schizophrenia-related mutation L607F in human or the corresponding L604F in mouse was essentially indistinguishable from the wild type (WT) as long as monitored by fluorescence, circular dichroism, ultracentrifugation, dynamic light scattering and nuclear magnetic resonance, the atomic force microscopy was able to detect their morphological distinctions. The WT peptides were round and well dispersed, while mutants were inhomogeneous and disrupted to form dimer to trimer that aligned along one direction without apparent aggregate formation. Homozygous L604F mutant mice created by CRISPR exhibited the significant decrease in DISC1 level in the immunohistopathology at the hippocampal region compared to the WTs. The ratio of prepulse inhibition of the homozygous mutant mice was significantly impaired compared to WTs. Altered DISC1 distribution or function caused by aberrant intermolecular interactions may contribute to information processing characteristics in schizophrenia.