The neurotrophin receptor, p75NTR, functions both as a low affinity, independent receptor and as a coreceptor with TrkA. In its independent function, it serves as an initiator of both pro- and antiapoptotic signaling pathways. It is one of a growing family of “dependence receptors”—receptors that confer cellular dependence on growth factors for life-or-death decision-making [19
The binding of nerve growth factor to the extracellular domain of p75NTR and the subsequent binding of a variety of interactor proteins with its intracellular domain result in the sequential cleavage of p75NTR by α
- and γ
-secretase to liberate the intracellular domain of p75NTR, p75ICD [20
]. We have previously demonstrated that p75ICD is sufficient for the variably pro- and antiapoptotic activities of p75NTR in some in vitro
]. An N-terminal segment of p75ICD has been termed “Chopper” and has been shown to be proapoptotic in an in vitro
system in which holo-p75NTR is proapoptotic [13
]. In the present study, we asked the question of whether Chopper would, conversely, be antiapoptotic in an in vitro
system in which holo-p75NTR is antiapoptotic. That is, we tested the hypothesis that Chopper activity determines whether p75NTR is pro- or antiapoptotic in a given system.
The results we present are not consistent with this hypothesis. They demonstrate that Chopper is proapoptotic whether holo-p75NTR is pro- or antiapoptotic. The variability of the effects of p75NTR on cell survival is therefore not related to variability of the effects of Chopper.
While the tyrosine kinase receptors have long been known to modulate such processes as cell death, proliferation, protection, and differentiation in development and disease of the nervous system (reviewed in [21
]), the involvement of p75NTR in development and disease is much less well characterized (reviewed in [22
]). However, recent studies make it likely that p75NTR plays different roles in Alzheimer's disease [1
], Parkinson's disease [4
], differentiation and synaptic connectivity along the neuraxis [23
], resistance of neural tumors to chemotherapy [6
], and migration of glioblastoma cells away from the primary tumor [5
Expression of p75NTR in the central nervous system is developmentally restricted such that, as humans progress from embryonic life to adulthood, p75NTR goes from ubiquitous expression to expression largely limited to cholinergic neurons in the basal forebrain and hippocampus (reviewed in [22
]). In addition, p75NTR and amyloid precursor protein (APP) have been shown to interact and, in their interaction, to induce neuronal death. p75NTR influences processing of APP and both NGF and β
-amyloid alter the p75NTR-APP interaction [24
]. Furthermore, p75NTR is a substrate for presenilin-1 and the two are coregulated in model systems and during normal development [1
]. These observations have implicated p75NTR in the pathogenesis of Alzheimer's disease.
The proNGF-sortillin-p75NTR complex has been implicated in apoptosis associated with Parkinson's disease. This complex has been suggested as a potential target in the prevention of degeneration of neurons in the substantia nigra [4
Pruning of axons during developmental neurite outgrowth has recently been shown to be a p75NTR-dependent process [25
]. Brain-derived neurotrophic factor (BDNF) is the cognate p75NTR ligand that orchestrates activity-dependent persistence of axons during development. Those axons that are less active degenerate in a process that requires p75NTR.
Resistance of PC12 pheochromocytoma cells to chemotherapy [6
], potentiation of neuroblastoma cell death after oxidative chemotherapy [26
], and migration away from the primary tumor with central nervous system invasiveness of glioblastomas [5
] all depend critically on p75NTR.
Understanding the structural and molecular underpinnings of p75NTR function and its context dependence may therefore identify novel targets for the treatment or prevention of neurodegenerative disease, developmental aberrations of the nervous system, and nervous system cancer. Molecular “dissection” of p75ICD may facilitate functional segregation of its pro- and antiapoptotic effects and facilitate manipulation of one or the other of the signaling cascades triggered by p75NTR and involved in specific pathologic or developmental processes. The results of the present study raise the question of whether Chopper-free fragments of p75NTR or p75ICD might be prototypes for antioxidant and antiapoptotic therapeutic strategies in the nervous system.