Glycogen synthase kinase-3 beta (GSK-3 beta) is a crucial component in the cascade of events that culminate in a range of neuro-degenerative diseases. It is controlled by several pathways, including calpain-mediated cleavage. Calpain mediates in cell death induced by 3-nitropropionic acid (3-NP), but GSK-3 beta regulation has not been demonstrated. Here we studied changes in total GSK-3 beta protein levels and GSK-3 beta phosphorylation at Ser-9 in this model. The 3-NP treatment induced GSK-3 beta truncation. This regulation was dependent on calpain activation, since addition of calpeptin to the medium prevented this cleavage. While calpain inhibition prevented 3-NP-induced neuronal loss, inhibition of GSK-3 beta by SB-415286 did not. Furthermore, inhibition of cdk5, a known target of calpain involved in 3-NP-induced cell death, also failed to rescue neurons in our model. Our results point to a new target of calpain and indicate possible cross-talk between calpain and GSK-3 beta in the 3-NP toxicity pathway. On the basis of our findings, we propose that calpain may modulate 3-NP-induced neuronal loss. (C) 2009 Wiley-Liss, Inc.
Regulation of GSK-3beta by calpain in the 3-nitropropionic acid model / N., Crespo Biel; A., Camins; J., Gutierrez Cuesta; Melchiorri, Daniela; Nicoletti, Ferdinando; M., Pallas; A. M., Canudas. - In: HIPPOCAMPUS. - ISSN 1050-9631. - STAMPA. - 20:8(2010), pp. 962-970. [10.1002/hipo.20691]
Regulation of GSK-3beta by calpain in the 3-nitropropionic acid model.
MELCHIORRI, Daniela;NICOLETTI, Ferdinando;
2010
Abstract
Glycogen synthase kinase-3 beta (GSK-3 beta) is a crucial component in the cascade of events that culminate in a range of neuro-degenerative diseases. It is controlled by several pathways, including calpain-mediated cleavage. Calpain mediates in cell death induced by 3-nitropropionic acid (3-NP), but GSK-3 beta regulation has not been demonstrated. Here we studied changes in total GSK-3 beta protein levels and GSK-3 beta phosphorylation at Ser-9 in this model. The 3-NP treatment induced GSK-3 beta truncation. This regulation was dependent on calpain activation, since addition of calpeptin to the medium prevented this cleavage. While calpain inhibition prevented 3-NP-induced neuronal loss, inhibition of GSK-3 beta by SB-415286 did not. Furthermore, inhibition of cdk5, a known target of calpain involved in 3-NP-induced cell death, also failed to rescue neurons in our model. Our results point to a new target of calpain and indicate possible cross-talk between calpain and GSK-3 beta in the 3-NP toxicity pathway. On the basis of our findings, we propose that calpain may modulate 3-NP-induced neuronal loss. (C) 2009 Wiley-Liss, Inc.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.