Faculty Research

Title

Proximal Giant Neurofilamentous Axonopathy in Mice Genetically Engineered to Resist Calpain and Caspase Cleavage of α-II Spectrin

Document Type

Article

Publication Date

2012

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 αII-spectrin (Spna2), a key protein in the maintenance of axonal integrity. Protein immunoblotting indicates that this reduction is due 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.

Comments

Publication Information.

Kassa, R., Monterroso, V., Wentzell, J., Ramos, A. L., Couchi, E., Lecomte, M. C., 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, 47(3), 631-638. doi:10.1007/s12031-011-9699-8

First Page

631

Last Page

638

DOI

10.1007/s12031-011-9699-8