Background. The intracellular domain (ICD) of the neurotrophin receptor, p75NTR, exhibits variably pro- and antiapoptotic activity and has been implicated in neurodegenerative and neurodestructive disease. The molecular determinants of these cellular effects are not completely understood. The “Chopper” domain of p75ICD has been shown to be proapoptotic in in vitro systems in which p75ICD is proapoptotic. The effects of Chopper in systems in which p75ICD is antiapoptotic and, therefore, whether or not Chopper accounts for the variability of the cellular effects of p75ICD are not known. We therefore examined the effects of deletion of Chopper on the effects of p75ICD on in vitro cell culture systems in which p75ICD is pro- or antiapoptotic, respectively. Results. In HN33.11 murine neuroblastoma-hippocampal neuron hybrid cells, p75ICD is antiapoptotic. In NIH 3T3 cells, p75ICD is proapoptotic. In both cell lines deletion of the Chopper domain from p75ICD decreases the incidence of apoptosis resulting from oxidative stress. Thus, irrespective of the nature of the effects of p75ICD on the cell, its Chopper domain is proapoptotic. Conclusions. Expression of p75ICD can enhance or attenuate oxidative induction of apoptosis. Variability of the effects of p75ICD is not related to variability of the effects of its Chopper domain. 1. Background The neurotrophin receptor, p75NTR, has been implicated in the pathogenesis of neurodegenerative and neurodestructive diseases, including Alzheimer’s disease [1–3], Parkinson’s disease [4], invasive glioblastoma [5], and chemoresistant neuroblastoma [6]. It can be pro- or antiapoptotic depending on the milieu in which it is expressed [6, 7]. Its activity appears to be mediated by its intracellular domain (p75ICD; [8, 9]). p75ICD can substitute for full-length p75NTR in both protective [8, 9] and death-inducing [7] models. p75NTR is a member of the tumor necrosis factor family of death receptors. As such, its C-terminal, CD95-like death domain was originally assumed to be responsible for its proapoptotic properties. However, the p75NTR death domain does not behave like the death domains of other tumor necrosis factor family death receptors [10–12]. The Chopper region at the juxtamembrane end of p75ICD has been shown to be both necessary and sufficient for apoptosis induction by p75NTR. Chopper must be either membrane-anchored or palmitoylated to function in this way; in fact, when it is not, it is a dominant negative influence on this activity in models in which p75NTR is proapoptotic [13]. We have characterized neural crest
References
[1]
Z. K. Mirnics, K. Mirnics, D. Terrano, D. A. Lewis, S. S. Sisodia, and N. F. Schor, “DNA microarray profiling of developing PS1-deficient mouse brain reveals complex and coregulated expression changes,” Molecular Psychiatry, vol. 8, no. 10, pp. 863–878, 2003.
[2]
K. Mirnics, Z. K. Mirnics, D. Arion et al., “Presenilin-1-dependent transcriptome changes,” Journal of Neuroscience, vol. 25, no. 6, pp. 1571–1578, 2005.
[3]
E. J. Coulson, L. M. May, A. M. Sykes, and A. S. Hamlin, “The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer's disease,” Neuroscientist, vol. 15, no. 4, pp. 317–323, 2009.
[4]
L. W. Chen, K. K. L. Yung, Y. S. Chan, D. K. Y. Shum, and J. P. Bolam, “The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson's disease,” CNS and Neurological Disorders, vol. 7, no. 6, pp. 512–523, 2008.
[5]
A. L. M. Johnston, X. Lun, J. J. Rahn et al., “The p75 neurotrophin receptor is a central regulator of glioma invasion,” PLoS Biology, vol. 5, no. 8, pp. 1723–1737, 2007.
[6]
C. Yan, Y. Liang, K. D. Nylander et al., “p75-nerve growth factor as an antiapoptotic complex: independence versus cooperativity,” Molecular Pharmacology, vol. 61, no. 4, pp. 710–719, 2002.
[7]
C. Yan, Z. K. Mirnics, C. F. Portugal et al., “Cholesterol biosynthesis and the pro-apoptotic effects of the p75 nerve growth factor receptor,” Molecular Brain Research, vol. 139, no. 2, pp. 225–234, 2005.
[8]
Y. Y. Tyurina, K. D. Nylander, Z. K. Mirnics et al., “The intracellular domain of p75NTR as a determinant of cellular reducing potential and response to oxidant stress,” Aging Cell, vol. 4, no. 4, pp. 187–196, 2005.
[9]
Z. Mi, D. A. Rogers, Z. K. Mirnics, and N. F. Schor, “P75NTR-dependent modulation of cellular handling of reactive oxygen species,” Journal of Neurochemistry, vol. 110, no. 1, pp. 295–306, 2009.
[10]
E. Liepinsh, L. L. Ilag, G. Otting, and C. F. Ibá？ez, “NMR structure of the death domain of the p75 neurotrophin receptor,” EMBO Journal, vol. 16, no. 16, pp. 4999–5005, 1997.
[11]
H. Kong, A. H. Kim, J. R. Orlinick, and M. V. Chao, “A comparison of the cytoplasmic domains of the Fas receptor and the p75 neurotrophin receptor,” Cell Death and Differentiation, vol. 6, no. 11, pp. 1133–1142, 1999.
[12]
E. J. Coulson, K. Reid, G. L. Barrett, and P. F. Bartlett, “p75 neurotrophin receptor-mediated neuronal death is promoted by Bcl-2 and prevented by Bcl-x(L),” Journal of Biological Chemistry, vol. 274, no. 23, pp. 16387–16391, 1999.
[13]
E. J. Coulson, K. Reid, M. Baca et al., “Chopper, a new death domain of the p75 neurotrophin receptor that mediates rapid neuronal cell death,” Journal of Biological Chemistry, vol. 275, no. 39, pp. 30537–30545, 2000.
[14]
H. J. Lee, D. N. Hammond, T. H. Large et al., “Neuronal properties and trophic activities of immortalized hippocampal cells from embryonic and young adult mice,” Journal of Neuroscience, vol. 10, no. 6, pp. 1779–1787, 1990.
[15]
Z. Korade, Z. Mi, and N. F. Schor, “Expression and p75 neurotrophin receptor dependence of cholesterol synthetic enzymes in adult mouse brain,” Neurobiology of Aging, vol. 28, no. 10, pp. 1522–1531, 2007.
[16]
M. W. Halterman, C. De Jesus, D. A. Rempe, N. F. Schor, and H. J. Federoff, “Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons,” Molecular and Cellular Neuroscience, vol. 38, no. 2, pp. 125–137, 2008.
[17]
L. Q. Jin, G. Cai, H. Y. Wang, C. Smith, and E. Friedman, “Characterization of the phosphoinositide-linked dopamine receptor in a mouse hippocampal-neuroblastoma hybrid cell line,” Journal of Neurochemistry, vol. 71, no. 5, pp. 1935–1943, 1998.
P. Mehlen and D. E. Bredesen, “The dependence receptor hypothesis,” Apoptosis, vol. 9, no. 1, pp. 37–49, 2004.
[20]
K. C. Kanning, M. Hudson, P. S. Amieux, J. C. Wiley, M. Bothwell, and L. C. Schecterson, “Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability,” Journal of Neuroscience, vol. 23, no. 13, pp. 5425–5436, 2003.
[21]
S. D. Skaper, “The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors,” CNS and Neurological Disorders, vol. 7, no. 1, pp. 46–62, 2008.
[22]
N. F. Schor, “The p75 neurotrophin receptor in human development and disease,” Progress in Neurobiology, vol. 77, no. 3, pp. 201–214, 2005.
[23]
K. Bartkowska, K. Turlejski, and R. L. Djavadian, “Neurotrophins and their receptors in early development of the mammalian nervous system,” Acta Neurobiologiae Experimentalis, vol. 70, no. 4, pp. 454–467, 2010.
[24]
J. Fombonne, S. Rabizadeh, S. Banwait, P. Mehlen, and D. E. Bredesen, “Selective vulnerability in Alzheimer's disease: amyloid precursor protein and p75NTR interaction,” Annals of Neurology, vol. 65, no. 3, pp. 294–303, 2009.
[25]
K. K. Singh, K. J. Park, E. J. Hong et al., “Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration,” Nature Neuroscience, vol. 11, no. 6, pp. 649–658, 2008.
[26]
V. Ganeshan and N. Schor, “The role of p75NTR and its signaling pathways in fenretinide-induced apoptosis in neuroblastoma cells,” Neurology, vol. 76, supplement 4, p. A 295, 2011.
