Survival mechanisms of peripheral sensory axons

DSpace/Manakin Repository

Survival mechanisms of peripheral sensory axons

Citable link to this page

 

 
Title: Survival mechanisms of peripheral sensory axons
Author: Pease, Sarah Elizabeth
Citation: Pease, Sarah Elizabeth. 2016. Survival mechanisms of peripheral sensory axons. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
Access Status: This work is under embargo until 2018-11-01
Full Text & Related Files:
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.
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:33840748
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters