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Cell Rep. 2019 Nov 19;29(8):2422-2437.e8. doi: 10.1016/j.celrep.2019.10.065.

The X-Linked Intellectual Disability Gene Zdhhc9 Is Essential for Dendrite Outgrowth and Inhibitory Synapse Formation.

Author information

1
Department of Cellular and Physiological Sciences, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
2
Michael Smith Laboratories, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
3
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada.
4
Department of Cellular and Physiological Sciences, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: shernaz.bamji@ubc.ca.

Abstract

Palmitoylation is a reversible post-translational lipid modification that facilitates vesicular transport and subcellular localization of modified proteins. This process is catalyzed by ZDHHC enzymes that are implicated in several neurological and neurodevelopmental disorders. Loss-of-function mutations in ZDHHC9 have been identified in patients with X-linked intellectual disability (XLID) and associated with increased epilepsy risk. Loss of Zdhhc9 function in hippocampal cultures leads to shorter dendritic arbors and fewer inhibitory synapses, altering the ratio of excitatory-to-inhibitory inputs formed onto Zdhhc9-deficient cells. While Zdhhc9 promotes dendrite outgrowth through the palmitoylation of the GTPase Ras, it promotes inhibitory synapse formation through the palmitoylation of another GTPase, TC10. Zdhhc9 knockout mice exhibit seizure-like activity together with increased frequency and amplitude of both spontaneous and miniature excitatory and inhibitory postsynaptic currents. These findings present a plausible mechanism for how the loss of ZDHHC9 function may contribute to XLID and epilepsy.

KEYWORDS:

Ras GTPase; TC10 GTPase; X-linked intellectual disability; Zdhhc9; dendrite growth; dendrite retraction; epilepsy; hippocampal culture; neuron morphology; palmitoylation; synapse

PMID:
31747610
DOI:
10.1016/j.celrep.2019.10.065
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