Survival mechanisms of peripheral sensory axons

Abstract

The ability to receive and process tactile information relies on proper interconnectivity of sensory neuron circuitry. Long peripheral sensory axons are necessary for rapid transmission of sensory information, and are particularly susceptible to degeneration, both during developmental pruning and in response to pathological insults such as injury. While axon degeneration mechanisms have been extensively studied, the opposing mechanisms of axon survival are not well understood. Here we use in vitro and in vivo methods to investigate intrinsic mechanisms governing axonal survival both during development and in response to chemotoxic injury. During development, sensory neurons compete for a limited supply of neurotrophic growth factors for survival. The subcellular location of neurotrophin stimulation dictates the survival response, as neurotrophin stimulation at the cell body is insufficient to support axon survival, while neurotrophin stimulation of the growing axonal process supports survival of the whole cell. In these studies we investigate transcriptional and post-translational changes induced by spatially distinct neurotrophin stimulation. Our studies suggest axonal neurotrophin stimulation preferentially upregulates protein synthesis components. These changes will enhance the translational capacity of the cell and may contribute to establishment of axonal connections. Following initial establishment of sensory circuitry, axon viability must be preserved throughout life to maintain circuit connectivity. Many chemotherapeutic agents can injure long-range axons, causing Chemotherapy-Induced Peripheral Neuropathy (CIPN), a syndrome characterized by impaired tactile sensation and persistent pain. Currently the molecular mechanisms of CIPN are not understood, and there are no available treatments. Here we show that paclitaxel, a chemotherapeutic agent, acts directly on sensory axons to cause axon degeneration by reductions in IP3-gated calcium flux and activation of the calcium-dependent protease calpain. Strikingly, Bclw, a Bcl2 family member, binds axonal type 1 IP3 receptors (IP3R1) and prevents this degenerative cascade, while other Bcl2 family members are not protective. Paclitaxel treatment selectively reduces expression of Bclw and thereby removes the brakes on this degenerative cascade. Together these data identify a mechanism for CIPN and indicate that selective Bclw-mimetics may provide a preventative therapy for this common disorder. Overall, these studies identify distinct and overlapping mechanisms involved in both developmental and pathological axon survival.