Ndrg2 deficiency ameliorates neurodegeneration in experimental autoimmune encephalomyelitis

• Published in: Journal of neurochemistry 2018-04, Vol.145 (2), p.139-153
• Main Authors: Le, Thuong Manh, Takarada‐Iemata, Mika, Ta, Hieu Minh, Roboon, Jureepon, Ishii, Hiroshi, Tamatani, Takashi, Kitao, Yasuko, Hattori, Tsuyoshi, Hori, Osamu
• Format: Article
• Language: English
• Subjects: Activation; AKT protein; Animals; Astrocytes; Central nervous system; Comparative analysis; Cytometry; Demyelination; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Excitatory Amino Acid Transporter 1 - metabolism; Excitatory Amino Acid Transporter 2 - metabolism; Experimental allergic encephalomyelitis; Flow cytometry; Gene expression; Gene silencing; Glial fibrillary acidic protein; Glutamic Acid - metabolism; Glutamic acid transporter; Immunohistochemistry; Inflammation; Inflammatory response; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple sclerosis; Myc protein; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurodegeneration; Proteins - genetics; Proteins - metabolism; Rodents; Spinal cord
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14294

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. In this study, we examined the expression and role of an astrocytic protein NDRG2 in experimental autoimmune encephalomyelitis, which is an animal model of multiple sclerosis. We observed that NDRG2 plays pathological roles in EAE most strongly at the step of neurodegeneration. NDRG2 regulates the expression of glutamate transporters through, at least in part, the PI3K/Akt signaling pathway. NDRG2‐expressiong astrocytes may be a novel target in MS and in other related diseases. Cover Image for this Issue: doi: 10.1111/jnc.14173.