Signaling by death receptors in the nervous system

Abstract

Cell death plays an important role both in shaping the developing nervous system and in neurological disease and traumatic injury. In spite of their name, death receptors can trigger either cell death or survival and growth. Recent studies implicate five death receptors--Fas/CD95, TNFR1 (tumor necrosis factor receptor-1), p75NTR (p75 neurotrophin receptor), DR4, and DR5 (death receptors-4 and -5)--in different aspects of neural development or degeneration. Their roles may be neuroprotective in models of Parkinson's disease, or pro-apoptotic in ALS and stroke. Such different outcomes probably reflect the diversity of transcriptional and posttranslational signaling pathways downstream of death receptors in neurons and glia.

Figure 1. Death receptor signaling pathways in neurons and glia

The two panels summarize novel aspects of death receptor signaling reviewed in the text. (A) Signaling events activated during cell death or degeneration. Once activated by their ligands (not shown, for clarity), death receptors cluster into multi-molecular assemblies in lipid rafts and trigger a series of post-translational and transcriptional events leading to caspase activation downstream of mitochondrial decision points. (B) Signaling events activated during cell survival or growth. Multiple control mechanisms act coordinately to prevent death receptor activation and inhibit downstream signaling. In addition, death receptors can stimulate signaling pathways directly associated with growth or survival.