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Determining the impact of impaired acylation on the nervous tissue using a novel mutant mice
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Advisor(s)
Abstract(s)
Normal cellular function is tightly controlled by various post-translational modifications. ZDHHC14, a member of the zinc-finger DHHC motif-containing enzymatic family, is predicted to mediate S-acylation of proteins, a process that greatly influences protein localization, association to membranes and stability. ZDHHC14 is highly expressed in the nervous system and its deficiency is often associated with the 6q25 microdeletion syndrome in patients with microencephaly, developmental delay and cognitive impairment. However, there is a knowledge gap with regards to ZDHHC14 activity, function and targets. To address this, a Zdhhc14 KO mice model was generated, using CRISPR-Cas9 technology, by deletion of exon 5. In this work, we characterized the expression of Zdhhc14 in WT and Zdhhc14 KO mice. Using cDNA prepared from brains of WT and Zdhhc14 KO mice, PCR analysis showed that deletion of exon 5 with its ensuing mutation, i.e., R235Lfs1*, leads to nonsense mRNA decay and virtually undetected Zdhhc14 mRNA in Zdhhc14 KO mice. We also determined that brain regions including corpus callosum, hippocampus and cortex, display the highest expression of Zdhhc14 mRNA. Following on preliminary neuropathological data, we investigated the effects of Zdhhc14 on central nervous system myelination. Using electron microscopy on optic nerves from WT and Zdhhc14 KO mice, we unraveled a defect in myelination characterized by reduced myelin thickness and increased number and length of myelin outfoldings. Moreover, measurement of myelin components, using western blot, revealed decreased expression of some myelin markers that could be related to impaired Zdhhc14 activity and may modulate myelin defects. Currently, our aim is to identify the substrates of Zdhhc14 activity (by comparing the palmitoylome of WT mice with that of Zdhhc14 KO mice) in order to better understand the biological processes and cellular functions of Zdhhc14, and the implications of its deficiency towards neuropathology and disease presentation.
Description
Keywords
S-acylation Zdhhc14 Nervous system Myelin Mouse
Pedagogical Context
Citation
Torres, G., Alves, N., & Brites, P. (2025). Determining the impact of impaired acylation on the nervous tissue using a novel mutant mice. Livro de Resumos do 18º Encontro de Investigação Jovem da U.Porto, 710–711. https://www.up.pt/ijup/wp-content/uploads/sites/892/2025/06/Livro-de-Resumos_IJUP-2025.pdf
Publisher
Universidade do Porto
CC License
Without CC licence