In Vivo Evidence That TRAF4 Is Required for Central Nervous System Myelin Homeostasis

Abstract

Tumor Necrosis Factor Receptor-Associated Factors (TRAFs) are major signal transducers for the TNF and interleukin-1/Toll-like receptor superfamilies. However, TRAF4 does not fit the paradigm of TRAF function in immune and inflammatory responses. Its physiological and molecular functions remain poorly understood. Behavorial analyses show that TRAF4-deficient mice (TRAF4-KO) exhibit altered locomotion coordination typical of ataxia. TRAF4-KO central nervous system (CNS) ultrastructure shows strong myelin perturbation including disorganized layers and disturbances in paranode organization. TRAF4 was previously reported to be expressed by CNS neurons. Using primary cell culture, we now show that TRAF4 is also expressed by oligodendrocytes, at all stages of their differentiation. Moreover, histology and electron microscopy show degeneration of a high number of Purkinje cells in TRAF4-KO mice, that was confirmed by increased expression of the Bax pro-apoptotic marker (immunofluorescence), TUNEL analysis, and caspase-3 activation and PARP1 cleavage (western blotting). Consistent with this phenotype, MAG and NogoA, two myelin-induced neurite outgrowth inhibitors, and their neuron partners, NgR and p75NTR were overexpressed (Q-RT-PCR and western blotting). The strong increased phosphorylation of Rock2, a RhoA downstream target, indicated that the NgR/p75NTR/RhoA signaling pathway, known to induce actin cytoskeleton rearrangement that favors axon regeneration inhibition and neuron apoptosis, is activated in the absence of TRAF4 (western blotting). Altogether, these results provide conclusive evidence for the pivotal contribution of TRAF4 to myelination and to cerebellar homeostasis, and link the loss of TRAF4 function to demyelinating or neurodegenerative diseases.

Astrocyte TNFR2 is required for CXCL12-mediated regulation of oligodendrocyte progenitor proliferation and differentiation within the adult CNS

“…In contrast, TNFR2 signaling is predominantly neuroprotective as shown by the use of TNFR2-selective agonist that rescues neurons from oxidative stress-induced cell death [15]. Consistent with this, TNFR2-deficient mice exhibit delayed repair in models of remyelination [2] and targeted deletion of tumor necrosis factor receptor associate-factor 4 (TRAF4), a major signal transducer for TNF-α led to ultrastructure perturbation in myelin [6]. These data suggest that therapeutic strategies that antagonize TNFR1 to limit inflammation and augment TNFR2 signaling to enhance remyelination might provide effective treatments that both ameliorate disease and promote recovery in MS patients.…”

Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin

“…Within the resistant H/W strain, these findings (overexpression of Sod3 and reduced expression of Ero1l) align with the reduced carcinogenic effects of TCDD. Traf4 is a common oncogene (Camilleri-Broet et al, 2007), however overexpression has also been shown to be essential for homeostasis of CNS myelination (Blaise et al, 2012).…”

A mosaic small supernumerary marker chromosome 17 in a patient with Tourette syndrome, ADHD and intellectual disability: A case story and review of the literature

“…Another gene within this region, TRAF4, encodes a family member of the tumor necrosis factor receptor-associated factors, which interacts with the neurotrophin receptor, p75 (NTR/NTSR1) and negatively regulates NTR induced cell death and NF-kappa B activation. TRAF4 is expressed in central nervous system neurons and in oligodendrocytes from early progenitors to mature myelinating cells (Blaise et al, 2012). TRAF4 has been shown to be involved in the subcellular localization of reactive oxygen species products in endothelial cells (Wu et al, 2005), in the maintenance of epithelial cell polarity and in the migration of dendritic cells.…”

“…TRAF4 has been shown to be involved in the subcellular localization of reactive oxygen species products in endothelial cells (Wu et al, 2005), in the maintenance of epithelial cell polarity and in the migration of dendritic cells. In addition, TRAF4 plays a role in proper myelination, and TRAF4-deficient mice exhibit altered locomotion probably due to Purkinje cell loss in the cerebellum (Blaise et al, 2012). This makes TRAF4 an attractive candidate gene for movement disorders, including TS.…”