Retrograde apoptotic signaling by the p75 neurotrophin receptor

Abstract

Neurotrophins are target-derived factors necessary for mammalian nervous system development and maintenance. They are typically produced by neuronal target tissues and interact with their receptors at axonal endings. Therefore, locally generated neurotrophin signals must be conveyed from the axon back to the cell soma. Retrograde survival signaling by neurotrophin binding to Trk receptors has been extensively studied. However, neurotrophins also bind to the p75 receptor, which can induce apoptosis in a variety of contexts. Selective activation of p75 at distal axon ends has been shown to generate a retrograde apoptotic signal, although the mechanisms involved are poorly understood. The present review summarizes the available evidence for retrograde proapoptotic signaling in general and the role of the p75 receptor in particular, with discussion of unanswered questions in the field. In-depth knowledge of the mechanisms of retrograde apoptotic signaling is essential for understanding the etiology of neurodegeneration in many diseases and injuries.

Keywords: JNK; NRIF; apoptosis; axonal transport; nerve growth factor; neurotrophin.

Figure 1. Apoptotic signaling mechanisms activated by the p75 receptor

Proapoptotic ligands bind to preexisting p75 dimers, resulting in recruitment of adaptor proteins such as NRAGE, TRAF6, and NRIF, leading to stimulation of JNK. The activation of JNK induces p75 proteolysis, first in the ECD by TACE, and then in the transmembrane domain by the γ-secretase complex. JNK can transcriptionally up-regulate TACE; however, there also appear to be other, more rapid mechanisms for stimulating this protease. The cleavage by γ-secretase releases p75’s ICD, resulting in a complex of the ICD, NRIF, a DNA-binding protein, and TRAF6 (T6), which promotes NRIF ubiquitylation (Ub). Ubiquitylated NRIF translocates to the nucleus and mediates apoptosis. In addition, this complex also leads to apoptosis through prolonged JNK activity.

Figure 2. Retrograde apoptotic signaling by p75

Many questions remain to be answered about retrograde signaling by p75 (indicated by question marks), including the mechanisms of internalization, the identity of the transport vesicle, where the cleavage occurs, and which fragments of p75 are transported, as well as which components are present in the retrograde signaling complex (e.g. various p75-binding partners).