Nervous NDRGs: the N-myc downstream–regulated gene family in the central and peripheral nervous system

Abstract

The N-Myc downstream-regulated gene (NDRG) family consists of four members (NDRG1, NDRG2, NDRG3, NDRG4) that are differentially expressed in various organs and function in important processes, like cell proliferation and differentiation. In the last couple of decades, interest in this family has risen due to its connection with several disorders of the nervous system including Charcot-Marie-Tooth disease and dementia, as well as nervous system cancers. By combining a literature review with in silico data analysis of publicly available datasets, such as the Mouse Brain Atlas, BrainSpan, the Genotype-Tissue Expression (GTEx) project, and Gene Expression Omnibus (GEO) datasets, this review summarizes the expression and functions of the NDRG family in the healthy and diseased nervous system. We here show that the NDRGs have a differential, relatively cell typespecific, expression pattern in the nervous system. Even though NDRGs share functionalities, like a role in vesicle trafficking, stress response, and neurite outgrowth, other functionalities seem to be unique to a specific member, e.g., the role of NDRG1 in myelination. Furthermore, mutations, phosphorylation, or changes in expression of NDRGs are related to nervous system diseases, including peripheral neuropathy and different forms of dementia. Moreover, NDRG1, NDRG2, and NDRG4 are all involved in cancers of the nervous system, such as glioma, neuroblastoma, or meningioma. All in all, our review elucidates that although the NDRGs belong to the same gene family and share some functional features, they should be considered unique in their expression patterns and functional importance for nervous system development and neuronal diseases.

Identification of DNA methylation markers for early detection of CRC indicates a role for nervous system-related genes in CRC

“…When investigating gene functions, we observed that twelve out of the top twenty (60.0%) genes were related to the nervous system based on their gene ontologies (Additional file 1 : Table S3), resembling the previously identified neuronal-specific expression of NDRG4 [ 27 – 29 ].…”

Investigating Glioblastoma Response to Hypoxia

“…NDRG1 was highly expressed in GB but not in LGG clinical samples compared to normal brain tissue ( Figure 8 A and Figure S6 ). NDRG1 is a multifaceted protein that has been shown to regulate nerve myelination, stress response, lipid biosynthesis and metabolism, exocytosis and differentiation [ 64 ]. NDRG1 has been shown to confer resistance to temozolomide, via binding and stabilization of MGMT [ 65 ].…”

N-MYC Downstream Regulated Gene 4 (NDRG4), a Frequent Downregulated Gene through DNA Hypermethylation, plays a Tumor Suppressive Role in Esophageal Adenocarcinoma

“…The role of NDRG4 in human cancers is quite controversial, in particular in tumors of the central nervous system [ 39 ]. In fact, NDRG4 is upregulated in tumors of central nerve system, such as glioblastoma [ 28 ] and meningioma [ 40 ], functioning as an oncogene.…”