The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury

A. Büki, Robert Siman, John Q. Trojanowski, John T. Povlishock

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

In animals and man, traumatic brain injury (TBI) results in axonal injury (AI) that contributes to morbidity and mortality. Such injured axons show progressive change leading to axonal disconnection. Although several theories implicate calcium in the pathogenesis of AI, experimental studies have failed to confirm its pivotal role. To explore the contribution of Ca2+-induced proteolysis to axonal injury, this study was undertaken in an animal model of TBI employing antibodies targeting both calpain-mediated spectrin proteolysis (CMSP) and focal neurofilament compaction (NFC), a marker of intra-axonal cytoskeletal perturbation, at 15-120 minutes (min) postinjury. Light microscopy (LM) revealed that TBI consistently evoked focal, intra-axonal CMSP that was spatially and temporally correlated with NFC. These changes were seen at 15 min postinjury with significantly increasing number of axons demonstrating CMSP immunoreactivity over time postinjury. Electron microscopy (EM) demonstrated that at 15 min postinjury CMSP was confined primarily to the subaxolemmal network. With increasing survival (30-120 min) CMSP filled the axoplasm proper. These findings provide the first direct evidence for focal CMSP in the pathogenesis of generalized/diffuse AI. Importantly, they also reveal an initial subaxolemmal involvement prior to induction of a more widespread axoplasmic change indicating a spatial-temporal compartmentalization of the calcium-induced proteolytic process that may be amenable to rapid therapeutic intervention.

Original languageEnglish
Pages (from-to)365-375
Number of pages11
JournalJournal of Neuropathology and Experimental Neurology
Volume58
Issue number4
Publication statusPublished - Apr 1999

Fingerprint

Spectrin
Calpain
Proteolysis
Wounds and Injuries
Intermediate Filaments
Axons
Diffuse Axonal Injury
Calcium
Microscopy
Electron Microscopy
Animal Models
Morbidity
Light
Survival
Mortality
Antibodies

Keywords

  • Axonal injury
  • Calcium
  • Calpain
  • Cytoskeleton
  • Immunohistochemistry
  • Spectrin
  • Traumatic brain injury

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury. / Büki, A.; Siman, Robert; Trojanowski, John Q.; Povlishock, John T.

In: Journal of Neuropathology and Experimental Neurology, Vol. 58, No. 4, 04.1999, p. 365-375.

Research output: Contribution to journalArticle

Büki, A. ; Siman, Robert ; Trojanowski, John Q. ; Povlishock, John T. / The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury. In: Journal of Neuropathology and Experimental Neurology. 1999 ; Vol. 58, No. 4. pp. 365-375.
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