Neu4, a gene encoding a sialidase, catalyzes the removal of sialic acid residues from glycoproteins, oligosaccharides, and sialylated glycolipids [1]. It has broad substrate specificity and is localized in the lysosome in mammals [1]. Sialidases are involved in numerous physiological processes, and thus Neu4 is potentially crucial for normal cellular function and organismal physiology. Gene knockout (KO) mouse models have been valuable in studying Neu4's function in vivo [1].

In Neu4 -/- mice, there was marked vacuolization and lysosomal storage in lung and spleen cells, along with an increased level of GD1a ganglioside and a decreased level of GM1 ganglioside in the brain [1]. These mice also showed neuroinflammation, as indicated by elevated GD1a and GT1b levels, increased LAMP1-positive lysosomal vesicles, Tunel-positive neurons, and changes in cytokine and chemokine expression [1]. Astrogliosis and microgliosis were enhanced in the hippocampus and cerebellum, accompanied by motor impairment [1]. In hepatocellular carcinoma (HCC), NEU4 expression was down-regulated, and overexpression of NEU4 inhibited cell motility by cleaving sialic acids on CD44 [2]. In ovarian carcinoma, a plasma membrane-localized isoform of NEU4 promoted peritoneal dissemination by desialylating and hyperactivating the epithelial growth factor receptor (EGFR) [3]. In kidney fibrosis, NEU4 expression was up-regulated, and its knockdown attenuated fibrosis while overexpression exacerbated it, with NEU4 interacting with Yes-associated protein (YAP) to promote fibrosis [4]. In glioblastoma stem cells (GSCs), NEU4 silencing triggered events like the activation of glycogen synthase kinase 3β, reduction of stem-like gene expression, and decreased GSC survival [5].

In summary, Neu4 plays essential roles in various biological processes and disease conditions. Mouse KO models have revealed its significance in neuroinflammation, cancer cell motility and metastasis, and kidney fibrosis. Understanding Neu4's function can potentially provide new treatment strategies for these diseases.

References:

1. Timur, Zehra Kevser, Inci, Orhan Kerim, Demir, Secil Akyildiz, Seyrantepe, Volkan. 2021. Sialidase neu4 deficiency is associated with neuroinflammation in mice. In Glycoconjugate journal, 38, 649-667. doi:10.1007/s10719-021-10017-9. https://pubmed.ncbi.nlm.nih.gov/34686927/

2. Zhang, Xiaoqing, Dou, Peng, Akhtar, Muhammad Luqman, Nie, Huan, Li, Yu. 2021. NEU4 inhibits motility of HCC cells by cleaving sialic acids on CD44. In Oncogene, 40, 5427-5440. doi:10.1038/s41388-021-01955-7. https://pubmed.ncbi.nlm.nih.gov/34282273/

3. Shi, Jie, Zhou, Rui, Wang, Shuo, Li, Jia, Wang, Longlong. 2024. NEU4-mediated desialylation enhances the activation of the oncogenic receptors for the dissemination of ovarian carcinoma. In Oncogene, 43, 3556-3569. doi:10.1038/s41388-024-03187-x. https://pubmed.ncbi.nlm.nih.gov/39402373/

4. Xiao, Ping-Ting, Hao, Jin-Hua, Kuang, Yu-Jia, Chen, Qian-Qian, Liu, E-Hu. 2024. Targeting Neuraminidase 4 Attenuates Kidney Fibrosis in Mice. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2406936. doi:10.1002/advs.202406936. https://pubmed.ncbi.nlm.nih.gov/39136142/

5. Silvestri, I, Testa, F, Zappasodi, R, Venerando, B, Tringali, C. 2014. Sialidase NEU4 is involved in glioblastoma stem cell survival. In Cell death & disease, 5, e1381. doi:10.1038/cddis.2014.349. https://pubmed.ncbi.nlm.nih.gov/25144716/