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

Abstract

SUMMARYTwo percent of all patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the palmitoylating enzyme,ZDHHC91, 2. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a disruption of white matter integrity3–6. We demonstrated that ablation ofZdhhc9in 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 inZDHHC9.