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Arch Biochem Biophys. 2014 Nov 15;562:1-8. doi: 10.1016/j.abb.2014.08.006. Epub 2014 Aug 21.

Role of calpain-1 in the early phase of experimental ALS.

Author information

1
National Research Council (C.N.R.), Institute of Marine Sciences (I.S.MAR.), U.O.S. of Genoa, Via De Marini, 6, 16149 Genoa, Italy; University of Genoa, Genoa, Italy; Department of Experimental Medicine (DI.ME.S.), Section of Biochemistry, Viale Benedetto XV, 1, 16132 Genoa, Italy; Center of Excellence for Biomedical Research (C.E.B.R.), Viale Benedetto XV, 9, 16132 Genoa, Italy. Electronic address: roberto.stifanese@ge.ismar.cnr.it.
2
University of Genoa, Genoa, Italy; Department of Experimental Medicine (DI.ME.S.), Section of Biochemistry, Viale Benedetto XV, 1, 16132 Genoa, Italy; Center of Excellence for Biomedical Research (C.E.B.R.), Viale Benedetto XV, 9, 16132 Genoa, Italy.
3
University of Genoa, Genoa, Italy; Department of Pharmacy (DI.FAR.), Pharmacology and Toxicology Unit, Viale Cembrano, 4, 16147 Genoa, Italy; Center of Excellence for Biomedical Research (C.E.B.R.), Viale Benedetto XV, 9, 16132 Genoa, Italy.

Abstract

Elevation in [Ca(2+)]i and activation of calpain-1 occur in central nervous system of SOD1(G93A) transgenic mice model of amyotrophic lateral sclerosis (ALS), but few data are available about the early stage of ALS. We here investigated the level of activation of the Ca(2+)-dependent protease calpain-1 in spinal cord of SOD1(G93A) mice to ascertain a possible role of the protease in the aetiology of ALS. Comparing the events occurring in the 120 day old mice, we found that [Ca(2+)]i and activation of calpain-1 were also increased in the spinal cord of 30 day old mice, as indicated by the digestion of some substrates of the protease such as nNOS, αII-spectrin, and the NR2B subunit of NMDA-R. However, the digestion pattern of these proteins suggests that calpain-1 may play different roles depending on the phase of ALS. In fact, in spinal cord of 30 day old mice, activation of calpain-1 produces high amounts of nNOS active species, while in 120 day old mice enhanced-prolonged activation of calpain-1 inactivates nNOS and down-regulates NR2B. Our data reveal a critical role of calpain-1 in the early phase and during progression of ALS, suggesting new therapeutic approaches to counteract its onset and fatal course.

KEYWORDS:

ALS; Ca(2+)-dependent proteolysis; Calpain; NMDA-R; NR2B; Neurodegeneration; SOD1/G93A transgenic mice; nNOS

PMID:
25151305
DOI:
10.1016/j.abb.2014.08.006
[Indexed for MEDLINE]

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