Dysmyelination by Oligodendrocyte‐Specific Ablation of Ninj2 Contributes to Depressive‐Like Behaviors

Abstract

Depression is a mental disorder affecting more than 300 million people in the world. Abnormalities in white matter are associated with the development of depression. Here, the authors show that mice with oligodendrocyte-specific deletion of Nerve injury-induced protein 2 (Ninj2) exhibit depressive-like behaviors. Loss of Ninj2 in oligodendrocytes inhibits oligodendrocyte development and myelination, and impairs neuronal structure and activities. Ninj2 competitively inhibits TNF𝜶/TNFR1 signaling pathway by directly binding to TNFR1 in oligodendrocytes. Loss of Ninj2 activates TNF𝜶-induced necroptosis, and increases C-C Motif Chemokine Ligand 2 (Ccl2) production, which might mediate the signal transduction from oligodendrocyte to neurons. Inhibition of necroptosis by Nec-1s administration synchronously restores oligodendrocyte development, improves neuronal excitability, and alleviates depressive-like behaviors. This study thus illustrates the role of Ninj2 in the development of depression and myelination, reveals the relationship between oligodendrocytes and neurons, and provides a potential therapeutic target for depression.

Brain region dependent molecular signatures and myelin repair following chronic demyelination

“…Volcano plots of the DEGs between 5 + 1 weeks vs. 3 weeks samples revealed highly significant upregulation of genes associated with myelinating oligodendrocytes, including Mag, Mbp , tight-junction claudins ( Cldn14, Cldn11 ), gap-junction connexin-47 ( Gjc2 ) and connexin-32 ( Gjb1 ), Pdlim2, lysophosphatidic acid receptor 1 (Lpar1), fatty acid hydroxylase (Fa2h), and gelsolin (Gsn) ( Figure 3B , and Supplementary Table 1 ). The dataset also revealed other highly upregulated genes during active remyelination including Ninj2 (Ninjurin 2) ( Noroozi et al, 2019 ; Sun et al, 2022 ) and tropinins Tnni1 and Tnnt1 , suggesting their potential unrecognized roles in myelin repair. When the dataset was cross-compared with cell type-enriched genes ( Zhang et al, 2014 ), it became evident that the most robust transcriptional changes during acute remyelination (5 + 1 wk) versus demyelination (3 wk) were those of oligodendrocytes ( Supplementary Figures 3A–C and Supplementary Table 1 ).…”

Antidepressant effect of teriflunomide via oligodendrocyte protection in a mouse model

“…Apoptosis in glial cells and neurons plays a crucial role in depression pathology [ [44] , [45] , [46] ], with apoptosis and necroptosis of oligodendrocytes in the hippocampus contributing to demyelination and synaptic dysfunction [ 15 , 47 , 48 ]. We examined apoptosis-related proteins in the hippocampus using western blotting ( Fig.…”

NINJ2 deficiency inhibits preadipocyte differentiation and promotes insulin resistance through regulating insulin signaling

“…NINJ2 was also found to co‐immunoprecipitate with various RTKs in cancer cells, including EGFR, PDGFRα/β, and FGFR, and promote downstream AKT and ERK activation [22, 23]. NINJ2 was also found to interact with TNF receptor 1 (TNFR1), inhibiting TNF‐α recruitment to TNFR1, and to protect oligodendrocytes against canonical necroptosis [24]. Therefore, a comprehensive understanding of the interaction between NINJ2 and these receptors is of significance.…”