Molecular Neurobiology

, Volume 52, Issue 1, pp 696–709 | Cite as

Degradation of βII-Spectrin Protein by Calpain-2 and Caspase-3 Under Neurotoxic and Traumatic Brain Injury Conditions

  • Firas H. Kobeissy
  • Ming Cheng Liu
  • Zhihui Yang
  • Zhiqun Zhang
  • Wenrong Zheng
  • Olena Glushakova
  • Stefania Mondello
  • John Anagli
  • Ronald L. Hayes
  • Kevin K. W. Wang
Article
First Online:
Received:
Accepted:

Abstract

A major consequence of traumatic brain injury (TBI) is the rapid proteolytic degradation of structural cytoskeletal proteins. This process is largely reflected by the interruption of axonal transport as a result of extensive axonal injury leading to neuronal cell injury. Previous work from our group has described the extensive degradation of the axonally enriched cytoskeletal αII-spectrin protein which results in molecular signature breakdown products (BDPs) indicative of injury mechanisms and to specific protease activation both in vitro and in vivo. In the current study, we investigated the integrity of βII-spectrin protein and its proteolytic profile both in primary rat cerebrocortical cell culture under apoptotic, necrotic, and excitotoxic challenge and extended to in vivo rat model of experimental TBI (controlled cortical impact model). Interestingly, our results revealed that the intact 260-kDa βII-spectrin is degraded into major fragments (βII-spectrin breakdown products (βsBDPs)) of 110, 108, 85, and 80 kDa in rat brain (hippocampus and cortex) 48 h post-injury. These βsBDP profiles were further characterized and compared to an in vitro βII-spectrin fragmentation pattern of naive rat cortex lysate digested by calpain-2 and caspase-3. Results revealed that βII-spectrin was degraded into major fragments of 110/85 kDa by calpain-2 activation and 108/80 kDa by caspase-3 activation. These data strongly support the hypothesis that in vivo activation of multiple protease system induces structural protein proteolysis involving βII-spectrin proteolysis via a specific calpain and/or caspase-mediated pathway resulting in a signature, protease-specific βsBDPs that are dependent upon the type of neural injury mechanism. This work extends on previous published work that discusses the interplay spectrin family (αII-spectrin and βII-spectrin) and their susceptibility to protease proteolysis and their implication to neuronal cell death mechanisms.

Keywords

Cell death Neurodegeneration Protease TBI βII-Spectrin apoptotic Calpain-2 Caspase-3 

Abbreviations

TBI

Traumatic brain injury

αII-SBDPs

αII-Spectrin breakdown products

βsBDPs

βII-Spectrin breakdown products

BDPs

Breakdown products

CCI

Controlled cortical impact

EDTA

Ethylenediaminetetraacetic acid

MTX

Maitotoxin

NMDA

N-Methyl-d-aspartate

STS

Staurosporine

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Notes

Acknowledgments

We would like to thank Dr. Hussam Jourdi for his critical and thorough discussion. Special thanks to Mr. Danny Johnson for his technical support in animal surgeries and tissue collection. This work was supported by the National Institutes of Health grants R01 NS049175-01 and R01 NS052831-01 and the Department of Defense grant DAMD17-03-1-0066. KKW and RLH hold equity in Banyan Biomarkers, Inc., a company commercializing technology of detecting brain injury biomarkers. RLH and OG are employees at Banyan Biomarkers Inc.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Firas H. Kobeissy
    • 1
    • 4
  • Ming Cheng Liu
    • 1
  • Zhihui Yang
    • 1
  • Zhiqun Zhang
    • 1
  • Wenrong Zheng
    • 1
  • Olena Glushakova
    • 2
  • Stefania Mondello
    • 3
  • John Anagli
    • 2
  • Ronald L. Hayes
    • 2
  • Kevin K. W. Wang
    • 1
  1. 1.Center for Neuroproteomics and Biomarkers Research, Department of PsychiatryUniversity of FloridaGainesvilleUSA
  2. 2.Banyan Laboratory, Banyan Biomarkers, Inc.AlachuaUSA
  3. 3.Department of NeurosciencesUniversity of MessinaMessinaItaly
  4. 4.Faculty of Medicine, Department of Biochemistry and Molecular GeneticsAmerican University of BeirutBeirutLebanon

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