title: Axoplasmic reticulum Ca(2+) release causes secondary degeneration of spinal axons.
abstract: OBJECTIVE
  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(2+) stores in secondary axonal degeneration following spinal cord injury.
  
  
  METHODS
  We developed a 2-photon laser-induced spinal cord injury model to follow morphological and Ca(2+) changes in live myelinated spinal axons acutely following injury.
  
  
  RESULTS
  Transected axons "died back" within swollen myelin or underwent synchronous pan-fragmentation associated with robust Ca(2+) increases. Spared fibers underwent delayed secondary bystander degeneration. Reducing Ca(2+) 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(2+) release worsened these events.
  
  
  CONCLUSIONS
  Ca(2+) release from intra-axonal Ca(2+) 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(2+) entry from the extracellular space across cell membranes, and emphasizes that modulation of axonal Ca(2+) stores may be a key pharmacotherapeutic goal in spinal cord injury.
authors.affiliation: Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Kentucky Spinal Cord Injury Research Center and Departments of Neurological Surgery, Microbiology and Immunology, University of Louisville, Louisville, KY.
authors.forename: David P
authors.initials: DP
authors.lastname: Stirling
authors.forename: Karen
authors.initials: K
authors.lastname: Cummins
authors.forename: S R
authors.initials: SR
authors.lastname: Wayne Chen
authors.forename: Peter
authors.initials: P
authors.lastname: Stys
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001896:Boron Compounds / Q000627:therapeutic use; D002110:Caffeine / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D053685:Laser Therapy / Q000009:adverse effects; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology*; D058915:Purinergic P1 Receptor Antagonists / Q000627:therapeutic use; D012433:Ryanodine / Q000627:therapeutic use; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology*; D019284:Thapsigargin / Q000627:therapeutic use; D013997:Time Factors
chemical_list: C504876:2-aminoethoxydiphenylborane; D001426:Bacterial Proteins; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D058915:Purinergic P1 Receptor Antagonists; D019837:Ryanodine Receptor Calcium Release Channel; C054562:yellow fluorescent protein, Bacteria; D012433:Ryanodine; D002110:Caffeine; D019284:Thapsigargin; D002118:Calcium