Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion

Abstract

SUMMARY Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here, we provide evidence that primary hippocampal neurons from a 22q11.2 deletion mouse model [Df(16)A+/−] have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits can be prevented by introduction of enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene located in the 22q11.2 locus and they are also observed in primary cultures from Zdhhc8-deficient mice. We show that many of these deficits are also present in the hippocampus of adult Df(16)A+/− and Zdhhc8-deficient mice. Finally, we provide evidence that PSD95 is one of the substrates of ZDHHC8. Our analysis reveals that 22q11.2 microdeletion results in deficits in neuronal development and suggests that impaired neuronal protein palmitoylation contributes to many of these deficits.

Palmitoylation in Alzheimer⿿s disease and other neurodegenerative diseases

“…A subsequent study demonstrated that dhhc8-deficient mice showed a decrease in dendritic spine density [239] and disruption of axonal growth [240]. In contrast to the studies described above, several studies have demonstrated no association between dhhc8 gene and susceptibility to schizophrenia [236,[241][242][243][244][245][246].…”

Association between variants of zinc finger genes and psychiatric disorders: Systematic review and meta-analysis

“…ZDHHC8 is associated with the G2/M checkpoint in response to DNA damage, so one possibility is that the ZDHHC8 protein may modify or interact with regulatory molecules of the cell cycle (Sudo et al, 2007). Mukai et al found that ZDHHC8 palmitoylated postsynaptic density-95, an adaptor molecule that is known to modulate dendritic spines and possibly dendritic branches (Ho et al, 2011;Mukai et al, 2008). Another report found that DHHC8 binds and palmitoylates the PDZ domain-containing protein PICK1 at a cysteine residue that is essential for synaptic long-term depression in cultured mouse cerebellar Purkinje neurons (Thomas et al, 2013).…”

MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective

“…It has been observed that the DiGeorge 22q11.2 deletion syndrome, characterized by the hemizygous deletion of a 1-2 Mb region of chromosome 22, can be caused by microdeletions within the DiGeorge syndrome critical region 8 (Dgcr8) gene that affect miRNA processing, with a 30-fold increase in the prevalence of schizophrenia and schizoaffective disorder [62][63][64]. Analysis of an animal model carrying a hemizygous 1.3 Mb chromosomal deficiency on mouse chromosome 16 (Df(16)A+/− mice), which is syntenic to the 1.5 Mb 22q11.2 microdeletion, revealed a reduction of miR-185, which resided within the 22q11.2 locus and is a regulator of the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2), with concomitant abnormalities in dendritic morphogenesis and formation of hippocampal pyramidal neurons both in culture and in vivo [64][65][66]. Preclinical evidence revealed that haploinsufficiency of Dgcr8 in mice causes synaptic overexpression of SERCA2 and increases LTP, and SERCA2 levels have been reported to be elevated in postmortem brain tissues of patients with schizophrenia [67,68].…”