Ndrg2, a member of the N-myc downstream-regulated gene (NDRG) family, is principally expressed in astrocytes of the central nervous system. It is involved in cell proliferation and differentiation and is commonly regarded as a tumor suppressor. Ndrg2 may affect multiple processes such as apoptosis, astrogliosis, blood-brain barrier integrity, and glutamate clearance, and is associated with pathways like NF-κB/C3, Wnt/β-catenin, and the interaction with PPM1A [3]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In diabetic mice, Ndrg2 deficiency aggravated the activation of complement C3 by accelerating the phosphorylation of NF-κB, leading to synaptic injury and cognitive dysfunction, while its overexpression promoted astrocytic remodeling by inhibiting complement C3, thus attenuating synaptic injury and cognitive dysfunction, indicating its role in diabetes-associated cognitive dysfunction [1]. In the context of subarachnoid hemorrhage, Ndrg2 knockout in astrocytes inhibited MMP-9 expression and attenuated blood-brain barrier damage, as cytoplasmic Ndrg2 bound to PPM1A and restricted the dephosphorylation of Smad2/3 [2]. For ischemic stroke-related studies, Ndrg2 overexpression in OGD/R-treated astrocytes aggravated the loss of glucose metabolism and promoted ferroptosis through inhibiting Wnt/β-catenin signaling activation [4].

In conclusion, Ndrg2 plays essential roles in the central nervous system, influencing processes related to synaptic function, blood-brain barrier integrity, and astrocyte-mediated metabolism and ferroptosis. Studies using KO/CKO mouse models have revealed its significance in diabetes-associated cognitive dysfunction, subarachnoid hemorrhage-induced blood-brain barrier disruption, and ischemic stroke-related astrocyte-specific responses, providing insights into potential therapeutic strategies for these neurological conditions.

References:

1. Jiang, Tao, Li, Yansong, He, Shuxuan, Ma, Zhi, Wang, Qiang. 2023. Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction. In EBioMedicine, 93, 104653. doi:10.1016/j.ebiom.2023.104653. https://pubmed.ncbi.nlm.nih.gov/37329577/

2. Feng, Dayun, Zhou, Jinpeng, Liu, Haixiao, Zhang, Jian, Qu, Yan. 2022. Astrocytic NDRG2-PPM1A interaction exacerbates blood-brain barrier disruption after subarachnoid hemorrhage. In Science advances, 8, eabq2423. doi:10.1126/sciadv.abq2423. https://pubmed.ncbi.nlm.nih.gov/36179025/

3. Li, Xin, Wu, Xiuquan, Luo, Peng, Xiong, Lize. 2019. Astrocyte-specific NDRG2 gene: functions in the brain and neurological diseases. In Cellular and molecular life sciences : CMLS, 77, 2461-2472. doi:10.1007/s00018-019-03406-9. https://pubmed.ncbi.nlm.nih.gov/31834421/

4. Wu, Lin, Cheng, Yingying, Wang, Runfeng, Ma, Bo, Zhang, Zhiguo. . NDRG2 regulates glucose metabolism and ferroptosis of OGD/R-treated astrocytes by the Wnt/β-catenin signaling. In Journal of biochemical and molecular toxicology, 38, e23827. doi:10.1002/jbt.23827. https://pubmed.ncbi.nlm.nih.gov/39193856/