ProNGF Induces p75-Mediated Death of Oligodendrocytes following Spinal Cord Injury

Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
Neuron (Impact Factor: 15.05). 11/2002; 36(3):375-86. DOI: 10.1016/S0896-6273(02)01005-X
Source: PubMed


The neurotrophin receptor p75 is induced by various injuries to the nervous system, but its role after injury has remained unclear. Here, we report that p75 is required for the death of oligodendrocytes following spinal cord injury, and its action is mediated mainly by proNGF. Oligodendrocytes undergoing apoptosis expressed p75, and the absence of p75 resulted in a decrease in the number of apoptotic oligodendrocytes and increased survival of oligodendrocytes. ProNGF is likely responsible for activating p75 in vivo, since the proNGF from the injured spinal cord induced apoptosis among p75(+/+), but not among p75(-/-), oligodendrocytes in culture, and its action was blocked by proNGF-specific antibody. Together, these data suggest that the role of proNGF is to eliminate damaged cells by activating the apoptotic machinery of p75 after injury.

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    • "Ghrelin also inhibited p38MAPK activation in LPS-stimulated BV-2 cells (Fig. 1). Our data are in agreement with previous reports showing that proNGF induces cell death of oligodendrocytes after SCI [16,25,26]. Furthermore, these results suggest that ghrelin inhibited oligodendrocyte cell death by alleviating microglia activation in in vitro and can explain in part the underlying neuroprotective mechanism by ghrelin after SCI previously reported by our group [14]. "
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    ABSTRACT: Background Recently, we reported the antiapoptotic effect of ghrelin in spinal cord injury-induced apoptotic cell death of oligodendrocytes. However, how ghrelin inhibits oligodendrocytes apoptosis, is still unknown. Therefore, in the present study, we examined whether ghrelin inhibits microglia activation and thereby inhibits oligodendrocyte apoptosis. Methods Using total cell extracts prepared from BV-2 cells activated by lipopolysaccharide (LPS) with or without ghrelin, the levels of p-p38 phosphor-p38 mitogen-activated protein kinase (p-p38MAPK), phospho-c-Jun N-terminal kinase (pJNK), p-c-Jun, and pro-nerve growth factor (proNGF) were examined by Western blot analysis. Reactive oxygen species (ROS) production was investigated by using dichlorodihydrofluorescein diacetate. To examine the effect of ghrelin on oligodendrocyte cell death, oligodendrocytes were cocultured in transwell chambers of 24-well plates with LPS-stimulated BV-2 cells. After 48 hours incubation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling staining were assessed. Results Ghrelin treatment significantly decreased levels of p-p38MAPK, p-JNK, p-c-Jun, and proNGF in LPS-stimulated BV-2 cells. ROS production increased in LPS-stimulated BV-2 cells was also significantly inhibited by ghrelin treatment. In addition, ghrelin significantly inhibited oligodendrocyte cell death when cocultured with LPS-stimulated BV-2 cells. Conclusion Ghrelin inhibits oligodendrocyte cell death by decreasing proNGF and ROS production as well as p38MAPK and JNK activation in activated microglia as an anti-inflammatory hormone.
    Full-text · Article · Sep 2014
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    • "p75NTR is upregulated following many injury paradigms, including seizures (Friedman, 2010). The best characterized role for p75NTR following injury is to induce apoptosis, particularly in response to proneurotrophins (Beattie et al., 2002; Troy et al., 2002; Harrington et al., 2004). Therefore, we evaluated changes in p75NTR following KA- or pilocarpine-induced SE. "
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    ABSTRACT: ProNGF and p75(NTR) are upregulated and induce cell death following status epilepticus (SE) in rats. However, less is known about the proneurotrophin response to SE in mice, a more genetically tractable species where mechanisms can be more readily dissected. We evaluated the temporal- and cell-specific induction of the proneurotrophins and their receptors, including p75(NTR), sortilin, and sorCS2, following mild SE induced with kainic acid (KA) or severe SE induced by pilocarpine. We found that mature NGF, p75(NTR), and proBDNF were upregulated following SE, while proNGF was not altered, indicating potential mechanistic differences between rats and mice. ProBDNF was localized to mossy fibers and microglia following SE. p75(NTR) was transiently induced primarily in axons and axon terminals following SE, as well as in neuron and astrocyte cell bodies. ProBDNF and p75(NTR) increased independently of cell death and their localization was different depending on the severity of SE. We also examined the expression of proneurotrophin co-receptors, sortilin and sorCS2. Following severe SE, sorCS2, but not sortilin, was elevated in neurons and astrocytes. These data indicate that important differences exist between rat and mouse in the proneurotrophin response following SE. Moreover, the proBDNF and p75(NTR) increase after seizures in the absence of significant cell death suggests that proneurotrophin signaling may play other roles following SE.
    Full-text · Article · Jul 2014 · ASN Neuro
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    • "In contrast to their mature counterparts , proNTs induce apoptosis, growth cone collapse, and facilitate synaptic retraction by a mechanism that requires p75 NTR but is independent of Trk receptors (Lee et al., 2001; Nykjaer et al., 2004; Rö sch et al., 2005; Woo et al., 2005; Yano et al., 2009). The capacity of proNTs to induce apoptosis is considered particularly important in conditions of acute and insidious neuronal and glial cell degeneration such as spinal cord and peripheral nerve injury, seizure, and aging (Arancio and Chao, 2007; Beattie et al., 2002; Ibá n ˜ ez and Simi, 2012; Nykjaer et al., 2005; Petratos et al., 2003). "
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    ABSTRACT: Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.
    Full-text · Article · Jun 2014 · Neuron
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