Regulation of dendrite morphology and excitatory synapse formation by zDHHC15

Shah, Bhavin S.; Shimell, Jordan J.; Bamji, Shernaz X.

doi:10.1242/jcs.230052

Cited by 36 publications

(36 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A zebrafish model for mutant zdhhc15b showed impairment in learning and memory behaviors in a T-maze test as well as reduced number of dopaminergic neurons and levels of TH and DAT proteins 44 . Zdhhc15 knockdown in cultured rat hippocampus neurons by shRNA was found to inhibit dendritic outgrowth and formation of mature spines 45 . Zdhhc15 -KO mice show normal number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Zdhhc15 , located at Xq13.3 in humans, encodes a protein palmitoyltransferase that is highly expressed in brain tissues 44 – 46 . Zdhhc15 knockdown was shown to reduce number and maturation state of dopaminergic neurons in zebrafish 44 and to decrease dendritic outgrowth, arborization, and spine maturation in cultured rat hippocampal neurons 45 . In vitro palmitoylation assays identified multiple ZDHHC15 substrates including PSD95 (postsynaptic density protein 95), CSP (Cysteine String Protein), DAT, GAP-43 (Growth Associated Protein 43), SNAP25b (Synaptosome Associated Protein 25, variant b), Sortilin, and Stathmin-2 47 .…”

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice

et al. 2021

View full text Add to dashboard Cite

Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice

et al. 2021

View full text Add to dashboard Cite

show abstract

“…To determine whether Zdhhc5 is involved in dendritic arborization and/or the formation of excitatory and inhibitory synapses, hippocampal neurons were transfected with eGFP plus the indicated constructs and immunostained for PSD-95 and gephyrin (faithful markers of excitatory and inhibitory synapses, respectively (Brigidi et al, 2015;Shah et al, 2019;Shimell et al, 2019); masking shown in Supplementary Figure 1A, B). While Zdhhc5 knockdown did not impact dendritic length ( Figure 1A), complexity ( Figure 1B Figure 1B for the creation of masks to quantify synaptic marker density).…”

Section: Zdhhc5 Promotes Excitatory Synapse Formation and Regulates Smentioning

confidence: 99%

Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

Shimell

Globa

Sepers

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5’s enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

show abstract

“…ZDHHC15 belongs to a super-family of PATs that catalyze the attachment of palmitate to other protein substrates [26,27]. To identify the role of ZDHHC15 in protein palmitoylation in GSCs, we performed an ABE assay to identify proteins that are S-acylated by ZDHHC15 ( Figure 4A).…”

Section: Identi Cation Of Palmitoylation Proteins Mediated By Zdhhc15mentioning

confidence: 99%

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

Fan

Yang

Zhao

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundA large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms.MethodsThe effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., cell counting kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The Acyl biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs.ResultsIn this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. ConclusionsIn conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

show abstract

Regulation of dendrite morphology and excitatory synapse formation by zDHHC15

Cited by 36 publications

References 40 publications

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice

Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice

Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

Contact Info

Product

Resources

About