ZDHHC15, a member of the Zinc finger DHHC-type palmitoyltransferases family, participates in protein palmitoylation, a common post-translational lipid modification in the brain. It is involved in various physiological activities in the brain and may be associated with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway [1,5]. Protein palmitoylation mediated by ZDHHC15 is crucial for the normal development and function of neuronal connections [2].

In animal models, loss-of-function mutations in Drosophila orthologs of ZDHHC15 cause flight and coordinated movement defects, expanding its role to motor dysfunction [3]. Zdhhc15-KO mice show increased novelty-induced locomotion, sensitivity to amphetamine, and elevated extracellular dopamine in the striatum, suggesting ZDHHC15-mediated palmitoylation as a regulatory mechanism of dopamine in the striatum [4]. In glioma research, knockdown of ZDHHC15 in glioma cells inhibits their proliferation and migration, and ZDHHC15 is identified as an independent prognostic biomarker with higher expression predicting a poorer prognosis [1]. Also, local anesthetics may target ZDHHC15-mediated GP130 palmitoylation to impair glioblastoma stem cell growth [6], and CK2α-mediated ZDHHC15 phosphorylation drives c-MET palmitoylation and glioblastoma stem cell tumorigenicity [7].

In conclusion, ZDHHC15 is essential for protein palmitoylation in the brain, influencing neuronal development, motor function, and dopamine regulation. In disease areas, it is significantly associated with glioma malignancy and may be a potential therapeutic target for glioblastoma. Research on ZDHHC15 knockout models has provided valuable insights into its role in these biological processes and disease conditions.

References:

1. Liu, Zhen-Yuan, Lan, Tian, Tang, Feng, Wang, Ze-Fen, Li, Zhi-Qiang. 2023. ZDHHC15 promotes glioma malignancy and acts as a novel prognostic biomarker for patients with glioma. In BMC cancer, 23, 420. doi:10.1186/s12885-023-10883-6. https://pubmed.ncbi.nlm.nih.gov/37161425/

2. Shah, Bhavin S, Shimell, Jordan J, Bamji, Shernaz X. 2019. Regulation of dendrite morphology and excitatory synapse formation by zDHHC15. In Journal of cell science, 132, . doi:10.1242/jcs.230052. https://pubmed.ncbi.nlm.nih.gov/31189538/

3. Lewis, Sara A, Bakhtiari, Somayeh, Heim, Jennifer, Padilla-Lopez, Sergio R, Kruer, Michael C. 2021. Mutation in ZDHHC15 Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability. In Neurology. Genetics, 7, e602. doi:10.1212/NXG.0000000000000602. https://pubmed.ncbi.nlm.nih.gov/34345675/

4. Mejias, Rebeca, Rodriguez-Gotor, Juan J, Niwa, Minae, Cadet, Jean-Lud, Wang, Tao. 2021. Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice. In Translational psychiatry, 11, 65. doi:10.1038/s41398-020-01194-6. https://pubmed.ncbi.nlm.nih.gov/33462194/

5. Tang, Feng, Yang, Chao, Li, Feng-Ping, Wang, Ze-Fen, Li, Zhi-Qiang. 2022. Palmitoyl transferases act as potential regulators of tumor-infiltrating immune cells and glioma progression. In Molecular therapy. Nucleic acids, 28, 716-731. doi:10.1016/j.omtn.2022.04.030. https://pubmed.ncbi.nlm.nih.gov/35664705/

6. Fan, Xiaoqing, Yang, Haoran, Zhao, Chenggang, Fang, Zhiyou, Chen, Xueran. 2021. Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation. In Stem cell research & therapy, 12, 107. doi:10.1186/s13287-021-02175-2. https://pubmed.ncbi.nlm.nih.gov/33541421/

7. Wang, Yang, Chen, Zhengxin, Li, Rui, Ji, Jing, Wang, Huibo. 2025. S-palmitoylation of c-MET by CK2α-mediated zDHHC15 phosphorylation drives glioblastoma stem cell tumorigenicity. In Neuro-oncology, , . doi:10.1093/neuonc/noaf098. https://pubmed.ncbi.nlm.nih.gov/40207776/