Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, United Kingdom.
Exp Neurol. 2018 Oct;308:35-46. doi: 10.1016/j.expneurol.2018.06.014. Epub 2018 Jun 23.
Protein S-acylation is a widespread post-translational modification that regulates the trafficking and function of a diverse array of proteins. This modification is catalysed by a family of twenty-three zDHHC enzymes that exhibit both specific and overlapping substrate interactions. Mutations in the gene encoding zDHHC9 cause mild-to-moderate intellectual disability, seizures, speech and language impairment, hypoplasia of the corpus callosum and reduced volume of sub-cortical structures. In this study, we have undertaken behavioural phenotyping, magnetic resonance imaging (MRI) and isolation of S-acylated proteins to investigate the effect of disruption of the Zdhhc9 gene in mice in a C57BL/6 genetic background. Zdhhc9 mutant male mice exhibit a range of abnormalities compared with their wild-type littermates: altered behaviour in the open-field test, elevated plus maze and acoustic startle test that is consistent with a reduced anxiety level; a reduced hang time in the hanging wire test that suggests underlying hypotonia but which may also be linked to reduced anxiety; deficits in the Morris water maze test of hippocampal-dependent spatial learning and memory; and a 36% reduction in corpus callosum volume revealed by MRI. Surprisingly, membrane association and S-acylation of H-Ras was not disrupted in either whole brain or hippocampus of Zdhhc9 mutant mice, suggesting that other substrates of this enzyme are linked to the observed changes. Overall, this study highlights a key role for zDHHC9 in brain development and behaviour, and supports the utility of the Zdhhc9 mutant mouse line to investigate molecular and cellular changes linked to intellectual disability and other deficits in the human population.
蛋白质 S-酰化是一种广泛存在的翻译后修饰，可调节多种蛋白质的运输和功能。这种修饰由 23 种 zDHHC 酶家族催化，这些酶具有特异性和重叠的底物相互作用。编码 zDHHC9 的基因突变可导致轻度至中度智力障碍、癫痫、言语和语言障碍、胼胝体发育不全和皮质下结构体积减少。在这项研究中，我们进行了行为表型分析、磁共振成像（MRI）和 S-酰化蛋白的分离，以研究 C57BL/6 遗传背景下 Zdhhc9 基因缺失对小鼠的影响。与野生型同窝仔相比，Zdhhc9 突变雄性小鼠表现出一系列异常：在开阔场测试、高架十字迷宫和声音惊吓测试中行为改变，表明焦虑水平降低；悬线测试中的悬停时间减少，提示潜在的低张力，但也可能与焦虑降低有关；在水迷宫测试中，海马依赖性空间学习和记忆能力受损；MRI 显示胼胝体体积减少 36%。令人惊讶的是，在 Zdhhc9 突变小鼠的全脑或海马中，H-Ras 的膜结合和 S-酰化并未受到破坏，这表明该酶的其他底物与观察到的变化有关。总的来说，这项研究强调了 zDHHC9 在大脑发育和行为中的关键作用，并支持使用 Zdhhc9 突变小鼠系来研究与人类智力障碍和其他缺陷相关的分子和细胞变化。
