Axoplasmic reticulum Ca2+ release causes secondary degeneration of spinal axons. Issue 2 (18th February 2014)

• Record Type: Journal Article
• Authors: Stirling, David P.; Cummins, Karen; Wayne Chen, S. R.; Stys, Peter
• Is Part Of: Annals of neurology. Volume 75:Issue 2(2014:Feb.)
• Page Start: 220
• Page End: 229
• Publication Date: 2014-02-18
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24099
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24099-sec-0001" sec-type="section"> <title>Objective</title> <p>Transected axons of the central nervous system fail to regenerate and instead die back away from the lesion site, resulting in permanent disability. Although both intrinsic (eg, microtubule instability, calpain activation) and extrinsic (ie, macrophages) processes are implicated in axonal dieback, the underlying mechanisms remain uncertain. Furthermore, the precise mechanisms that cause delayed "bystander" loss of spinal axons, that is, ones that were not directly damaged by the initial insult, but succumbed to secondary degeneration, remain unclear. Our goal was to evaluate the role of intra‐axonal Ca<sup>2+</sup> stores in secondary axonal degeneration following spinal cord injury.</p> </sec> <sec id="ana24099-sec-0002" sec-type="section"> <title>Methods</title> <p>We developed a 2‐photon laser‐induced spinal cord injury model to follow morphological and Ca<sup>2+</sup> changes in live myelinated spinal axons acutely following injury.</p> </sec> <sec id="ana24099-sec-0003" sec-type="section"> <title>Results</title> <p>Transected axons "died back" within swollen myelin or underwent synchronous pan‐fragmentation associated with robust Ca<sup>2+</sup> increases. Spared fibers underwent delayed secondary bystander degeneration. Reducing Ca<sup>2+</sup> release from axonal stores mediated by ryanodine and inositol triphosphate receptors significantly decreased axonal dieback and bystander injury. Conversely, a gain‐of‐function ryanodine receptor 2 mutant or pharmacological treatments that promote axonal store Ca<sup>2+</sup> release worsened these events.</p> </sec> <sec id="ana24099-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Ca<sup>2+</sup> release from intra‐axonal Ca<sup>2+</sup> stores, distributed along the length of the axon, contributes significantly to secondary degeneration of axons. This refocuses our approach to protecting spinal white matter tracts, where emphasis has been placed on limiting Ca<sup>2+</sup> entry from the extracellular space across cell membranes, and emphasizes that modulation of axonal Ca<sup>2+</sup> stores may be a key pharmacotherapeutic goal in spinal cord injury. Ann Neurol 2014;75:220–229</p> </sec> </abstract>