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The X‐Linked Intellectual Disability Gene, ZDHHC9 , Is Important for Oligodendrocyte Subtype Determination and Myelination
Author(s) -
White Rocio B.,
Wild Angela R.,
O'Leary Timothy P.,
Thompson Andrew J.,
Flibotte Stephane,
Peng Angie,
Rogalski Jason C.,
Mair Mila,
Derhami Neeki,
Bamji Shernaz X.
Publication year - 2025
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.70016
Subject(s) - oligodendrocyte , biology , corpus callosum , myelinogenesis , myelin , white matter , microbiology and biotechnology , neuroscience , genetics , central nervous system , medicine , radiology , magnetic resonance imaging
ABSTRACT Two percent of patients with X‐linked intellectual disability (XLID) exhibit loss‐of‐function mutations in the enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a concurrent disruption in white matter integrity. In this study, we demonstrate that deletion of Zdhhc9 in mice disrupts the balance of mature oligodendrocyte subtypes within the corpus callosum. While overall mature oligodendrocyte numbers are unchanged, there is a marked increase in MOL5/6 cells that are enriched in genes associated with cell adhesion and synapses, and a concomitant decrease in MOL2/3 cells that are enriched in genes associated with myelination. In line with this, we observed a decrease in the density of myelinated axons and disruptions in myelin compaction in the corpus callosum of Zdhhc9 knockout mice. RNA sequencing and proteomic analysis further revealed a reduction in genes and proteins essential for lipid metabolism, cholesterol synthesis, gene expression, and myelin compaction, offering insights into the underlying mechanisms of the pathology. These findings reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte subtype determination and myelinogenesis, offering mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9 .