The p75 neurotrophin receptor and neuronal apoptosis

Although evidence continues to accumulate for the apoptosis-inducing role o f the p75 neurotrophin receptor, several outstanding questions remain. One of these concerns the signal transduction pathway of p75, which continues t o be elusive. The evidence for the roles of ceramide, c-jun kinase and NF-k appa B is discussed: none of these are able to account satisfactorily for p 75 death signalling. Negative modulation of Trk signalling by p75 could acc ount for part of the pro-apoptotic effect, but is unlikely to be a major co mponent. Although recent evidence indicates that the juxtamembrane region i s critical for causing cell death, p75 has a well-conserved death domain. T his may be important for functions other than killing. In glial cells and s ome neurons that express p75 but not TrkA, p75 causes cell death in respons e to nerve growth factor (NGF) binding. In sensory neurons and PC12 cells, p75 appears to signal constitutively. In cholinergic forebrain neurons, p75 expression leads to atrophy and downregulation of cholinergic markers, rat her than cell death. The major challenges in p75 research are to define its signalling pathways, and particularly the intracellular proteins with whic h it interacts. Another major challenge is to develop a model that reconcil es the different facets of p75, such as its ability in some situations to a ssist TrkA to rescue NGF-dependent neurons, but to stimulate apoptosis in o thers. (C) 2000 Elsevier Science Ltd. All rights reserved.