Molecules in focus
The p75 neurotrophin receptor

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Abstract

The pan neurotrophin receptor (p75NTR) is best known for mediating neural cell death during development as well as in the adult following injury, the latter making it a target for the treatment of neurodegenerative disease. Although p75NTR has been studied for over 30 years, a number of recent discoveries have changed our understanding of its regulation. Here we provide a brief overview of the p75NTR protein, its post-translational modifications, and the phenotype of p75NTR-deficient mice as a starting point for researchers unfamiliar with this complex receptor. The accepted mechanisms underlying the ability of p75NTR to regulate cell death as well as a number of other neural functions, most notably neuronal differentiation, neurite outgrowth and synaptic plasticity, are also summarised.

Introduction

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 (Herrup & Shooter, 1973) as the receptor for the neurotrophin, nerve growth factor (NGF; p75NTR was first known as the NGFR), and was subsequently found to be a receptor for all the neurotrophins (NGF, brain-derived neurotrophic factor and neurotrophin-3). This also includes the immature pro-neurotrophin forms (Barker, 2004; Chao & Bothwell, 2002) which may, in part, explain the bifurcated role of p75NTR in regulating cell survival. The binding of pro-neurotrophins with p75NTR appears to be mediated by interaction with a co-receptor sortilin, a combination thought to promote apoptosis or growth inhibition. This is in contrast to the growth-promoting mature neurotrophin, p75NTR and tropomyosin receptor kinase (trk) receptor complex within which p75NTR was first described (Barker, 2004; Fig. 1). Interestingly, the question of how p75NTR and trk couple to form a high-affinity survival receptor complex remains unresolved, but has been recently reinvigorated by ligand–receptor structural studies (Wehrman et al., 2007). Indeed, p75NTR is capable of interacting with an increasing list of co-receptors (including Nogo66 and Lingo; Barker, 2004; Bronfman & Fainzilber, 2004), apparently by a variety of different mechanisms. These co-receptor interactions are likely to be differentially regulated by post-translational modifications of p75NTR, its cellular location, and the state of cellular differentiation, such that the second messengers, by which p75NTR mediates its array of functions (Fig. 1), can be specifically activated.

Section snippets

Structure

p75NTR is a type I transmembrane protein, with its molecular weight (75 kDa) determined by glycosylation through both N- and O-linkages in the extracellular domain (Grob, Ross, Koprowski, & Bothwell, 1985; Johnson et al., 1986; Fig. 2). It is the 16th member of the tumour necrosis factor receptor (TNFR) death-inducing superfamily, due to its highly conserved cysteine-rich repeat structures of the extracellular ligand binding site (Fig. 2). A sub-group of TNFR family members, including p75NTR,

Expression, activation and turnover

p75NTR is widely expressed in the developing central and peripheral nervous system during the period of synaptogenesis and developmental cell death (Davies, 1991). Expression is generally down-regulated in the adult but is again up-regulated following injury. The promoter region and factors regulating p75NTR expression are relatively uncharacterised. Once expressed, p75NTR can be directed within the cell to the apical/axonal membranes through glycosylation, and to lipid raft sub-domains of the

Biological function

Although first identified for survival-promoting effects as a co-receptor for trk, p75NTR signal transduction appears to only play a subtle role in the phosphorylation survival cascade initiated by trk receptors (Miller & Kaplan, 2001). In contrast, p75NTR is currently best known for its role in mediating neural cell death, and its death signalling cascade is generally well characterised. Death signalling is mediated via one or more of the receptor's intracellular binding partners, resulting in

Medical applications

p75NTR death signalling is implicated in a number of human neurodegenerative diseases, the most widely studied being Alzheimer's disease and motor neuron disease (MND), where elevated p75NTR expression is strongly correlated with neurodegeneration (Dechant & Barde, 2002). This link is also strong in animal models of MND, ischaemia, trauma and seizure (Dechant & Barde, 2002), where inhibiting the expression, activation or downstream signalling of p75NTR prevents cell loss and promotes improved

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