The X-Linked Intellectual Disability gene, ZDHHC9, is important for oligodendrocyte maturation and myelin formation

Two percent of all patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the palmitoylating enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a disruption of white matter integrity. We demonstrated that ablation of Zdhhc9 in mice substantially impairs the maturation of oligodendrocytes, resulting in fewer mature, myelinating oligodendrocytes, higher numbers of oligodendrocyte progenitor cells and a decrease in the density of myelinated axons. Ultrastructural analysis of the remaining myelinated axons in the corpus callosum revealed further disruptions in myelin integrity. RNA sequencing and proteomic analyses revealed a concomitant decrease in the expression of genes and proteins involved in lipid metabolism, cholesterol synthesis and myelin compaction. These results reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte differentiation and myelinogenesis and provide mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9. Wild-type and Zdhhc9 knockdown corpus callosum and optic nerve from mice were studied via RNA-seq using between 4 and 6 replicates for each tissue-genotype combination.在所有X连锁智力障碍（X-linked intellectual disability, XLID）患者中，2%的个体存在棕榈酰化酶ZDHHC9的功能丧失型突变。此类患者中观察到的主要解剖学缺陷之一，为胼胝体体积减小与白质完整性受损。本研究证实，敲除小鼠体内的Zdhhc9基因可显著损伤少突胶质细胞的成熟进程，具体表现为成熟髓鞘形成型少突胶质细胞数量减少、少突胶质细胞祖细胞数量增多，以及有髓轴突密度降低。对胼胝体中残留有髓轴突的超微结构分析显示，髓鞘完整性存在进一步破坏。RNA测序（RNA-seq）与蛋白质组学分析结果表明，参与脂质代谢、胆固醇合成及髓鞘致密化的基因与蛋白质的表达水平同步下降。上述研究结果揭示了ZDHHC9与蛋白质棕榈酰化在调控少突胶质细胞分化及髓鞘生成过程中此前未被充分认知的关键作用，并为阐释ZDHHC9突变患者白质体积缺陷的分子机制提供了新见解。本研究采用RNA-seq技术，对小鼠野生型与Zdhhc9敲低型的胼胝体及视神经组织展开分析，每组组织-基因型组合设置4至6个生物学重复。