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The role of X-linked intellectual disability-related gene, Zdhhc9, in white matter development

University of British Columbia

Protein palmitoylation, the process by which palmitic acid is reversibly added to protein substrates, is the most common post-translational lipid modification in the brain. Palmitoylation is facilitated by a family of palmitoyl acyltransferases, called Zdhhc enzymes, and a number of mutations in genes encoding these enzymes are associated with neurological disorders. Loss-of- function variants in the human ZDHHC9 gene have been identified in patients diagnosed with X- linked intellectual disability (XLID). Multiple clinical studies have shown that the brains of patients with ZDHHC9 mutations have regional changes in white matter content, including reductions in overall white matter volume and alterations in the microstructure of white matter tracts, and in vivo research has demonstrated that Zdhhc9 mice exhibit similar reductions in corpus callosum volume. This dissertation discusses work showing that Zdhhc9 is highly expressed in the corpus callosum and oligodendrocytes, and that loss of Zdhhc9 in vivo may impact myelin formation. Zdhhc9 expression is nearly two-fold higher in the corpus callosum than in any other region of the mouse brain, and is consistently enriched in oligodendrocyte expression data from multiple, independent RNA-seq studies. In the brains of Zdhhc9 knockout mice, there are significant reductions in the overall protein levels of myelin/myelinating oligodendrocyte-associated markers, MBP, MOG, and PLP, and in the palmitoylation levels of MOG and PLP. We also observed trends suggesting altered distribution of myelin in the primary visual cortex (V1) of Zdhhc9 knockout mice. This work provides new perspectives into the role of Zdhhc9 in oligodendrocytes and provides evidence that palmitoylation contributes to the development of white matter.

Text

2022-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75790

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/