Ndrg2 deficiency ameliorates neurodegeneration in experimental autoimmune encephalomyelitis

Abstract

N-myc downstream-regulated gene 2 (NDRG2) is a differentiation- and stress-associated molecule that is predominantly expressed in astrocytes in the central nervous system. In this study, we examined the expression and role of NDRG2 in experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis. Western blot and immunohistochemical analysis revealed that the expression of NDRG2 was observed in astrocytes of spinal cord, and was enhanced after EAE induction. A comparative analysis of wild-type and Ndrg2 mice revealed that deletion of Ndrg2 ameliorated the clinical symptoms of EAE. Although Ndrg2 deficiency only slightly affected the inflammatory response, based on the results of flow cytometry, qRT-PCR, and immunohistochemistry, it significantly reduced demyelination in the chronic phase, and, more importantly, neurodegeneration both in the acute and chronic phases. Further studies revealed that the expression of astrocytic glutamate transporters, including glutamate aspartate transporter (GLAST) and glutamate transporter 1, was more maintained in the Ndrg2 mice compared with wild-type mice after EAE induction. Consistent with these results, studies using cultured astrocytes revealed that Ndrg2 gene silencing increased the expression of GLAST, while NDRG2 over-expression decreased it without altering the expression of glial fibrillary acidic protein. The effect of NDRG2 on GLAST expression was associated with the activation of Akt, but not with the activation of nuclear factor-kappa B. These findings suggest that NDRG2 plays a key role in the pathology of EAE by modulating glutamate metabolism. Cover Image for this Issue: doi: 10.1111/jnc.14173.

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

“…This could be a potential mechanism as to why the expression of the glutamate transporters glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) were increased by deletion of NDRG2. An alternative explanation would be that the increased expression of glutamate transporters was caused by increased activation of Akt-signaling, as NDRG2 silencing resulted in increased levels of p-Akt [44].…”

“…In fact, the reduced glutamate receptor expression and concomitant glutamate toxicity in EAE can be counteracted by the NDRG2-induced upregulation of glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1). Due to this, demyelination and neurodegeneration, the characteristic features in multiple sclerosis, were significantly reduced [44].…”

Upregulation of P53 promotes nucleus pulposus cell apoptosis in intervertebral disc degeneration through upregulating NDRG2

“…NDRG2 has been shown to contribute to the pathogenesis of degenerative diseases (Cheng et al, 2020). NDRG2 downregulation inhibited neuron degeneration in autoimmune encephalomyelitis (Le et al, 2018), implying the potential effects of NDRG2 in other degenerative diseases, such as IVDD. NDRG2 has been shown to induce neuronal apoptosis in another neurodegenerative disease, Alzheimer's disease (Rong et al, 2017).…”

Overexpression of NDRG2 in skeletal muscle does not ameliorate the effects of stress in vivo

“…NDRG2 expression is induced in many in vitro and in vivo models of stress and disease, both in skeletal muscle and in other tissues, prompting investigation into its role during these conditions. For example, in astrocytes NDRG2 is induced after cerebral ischaemia (Takarada‐Iemata et al., 2018), during inflammation arising from a cortical stab injury (Takarada‐Iemata et al., 2014) and during experimental autoimmune encephalomyelitis (Le et al., 2018). However, investigations of the role of NDRG2 during these stressful conditions have had mixed findings.…”

“…However, investigations of the role of NDRG2 during these stressful conditions have had mixed findings. NDRG2 deficiency reduced spinal cord demyelination and neurodegeneration in mice with experimental autoimmune encephalomyelitis (Le et al., 2018) and attenuated astrogliosis and neuronal death after injury (Takarada‐Iemata et al., 2014). In contrast, NDRG2 deficiency increased neuronal infarction and inflammation after blood flow occlusion and ischaemia (Takarada‐Iemata et al., 2018).…”