Proximal giant neurofilamentous axonopathy in mice genetically engineered to resist calpain and caspase cleavage of α-II spectrin

R. Kassa, Victor Hugo Monterroso, J. Wentzell, A. L. Ramos, E. Couchi, M. C. Lecomte, M. Iordanov, D. Kretzschmar, G. Nicolas, D. Tshala-Katumbay

Research output: Contribution to journalArticle

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Abstract

We use 1,2-diacetylbenzene (1,2-DAB) to probe molecular mechanisms of proximal giant neurofilamentous axonopathy (PGNA), a pathological hallmark of amyotrophic lateral sclerosis. The spinal cord proteome of rodents displaying 1,2-DAB PGNA suggests a reduction in the abundance of α-II spectrin (Spna2), a key protein in the maintenance of axonal integrity. Protein immunoblotting indicates that this reduction is due to Spna2 degradation. We investigated the importance of such degradation in 1,2-DAB PGNA. Spna2 mutant mice lacking a calpain- and/or caspase-sensitive domain (CSD), thus hypothetically resistant to 1,2-DAB, and wild-type littermates, were treated with 1,2-DAB, 35 mg/kg/day, or saline control, for 3 weeks. 1,2-DAB induced motor weakness and PGNA, irrespective of the genotype. Spna2-calpain breakdown products were not detected in mutant mice, which displayed a normal structure of the nervous system under saline treatment. Intriguingly, treatment with 1,2-DAB reduced the abundance of the caspase-specific 120-kDa Spna2 breakdown products. Our findings indicate that degradation of Spna2 by calpain- and/or caspase is not central to the pathogenesis of 1,2-DAB axonopathy. In addition, the Spna2-CSD seems to be not required for the maintenance of the cytoskeleton integrity. Our conceptual framework offers opportunities to study the role of calpain-caspase cross talk, including that of the protease degradomics, in models of axonal degeneration.

Original languageEnglish (US)
Pages (from-to)631-638
Number of pages8
JournalJournal of Molecular Neuroscience
Volume47
Issue number3
DOIs
StatePublished - Jul 1 2012

Fingerprint

Spectrin
Calpain
Caspases
Maintenance
Molecular Probes
1,2-diacetylbenzene
Amyotrophic Lateral Sclerosis
Proteome
Cytoskeleton
Immunoblotting
Nervous System
Rodentia
Spinal Cord
Proteins
Peptide Hydrolases
Genotype

Keywords

  • 1,2-Diacetylbenzene
  • Calpain
  • Caspase
  • Neurodegeneration
  • α-II spectrin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Kassa, R., Monterroso, V. H., Wentzell, J., Ramos, A. L., Couchi, E., Lecomte, M. C., ... Tshala-Katumbay, D. (2012). Proximal giant neurofilamentous axonopathy in mice genetically engineered to resist calpain and caspase cleavage of α-II spectrin. Journal of Molecular Neuroscience, 47(3), 631-638. https://doi.org/10.1007/s12031-011-9699-8

Proximal giant neurofilamentous axonopathy in mice genetically engineered to resist calpain and caspase cleavage of α-II spectrin. / Kassa, R.; Monterroso, Victor Hugo; Wentzell, J.; Ramos, A. L.; Couchi, E.; Lecomte, M. C.; Iordanov, M.; Kretzschmar, D.; Nicolas, G.; Tshala-Katumbay, D.

In: Journal of Molecular Neuroscience, Vol. 47, No. 3, 01.07.2012, p. 631-638.

Research output: Contribution to journalArticle

Kassa, R, Monterroso, VH, Wentzell, J, Ramos, AL, Couchi, E, Lecomte, MC, Iordanov, M, Kretzschmar, D, Nicolas, G & Tshala-Katumbay, D 2012, 'Proximal giant neurofilamentous axonopathy in mice genetically engineered to resist calpain and caspase cleavage of α-II spectrin', Journal of Molecular Neuroscience, vol. 47, no. 3, pp. 631-638. https://doi.org/10.1007/s12031-011-9699-8
Kassa, R. ; Monterroso, Victor Hugo ; Wentzell, J. ; Ramos, A. L. ; Couchi, E. ; Lecomte, M. C. ; Iordanov, M. ; Kretzschmar, D. ; Nicolas, G. ; Tshala-Katumbay, D. / Proximal giant neurofilamentous axonopathy in mice genetically engineered to resist calpain and caspase cleavage of α-II spectrin. In: Journal of Molecular Neuroscience. 2012 ; Vol. 47, No. 3. pp. 631-638.
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AU - Ramos, A. L.

AU - Couchi, E.

AU - Lecomte, M. C.

AU - Iordanov, M.

AU - Kretzschmar, D.

AU - Nicolas, G.

AU - Tshala-Katumbay, D.

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