Article abstract
Nature Neuroscience 10, 436 - 443 (2007)
Published online: 18 March 2007 | doi:10.1038/nn1869
Rho mediates calcium-dependent activation of p38
and subsequent excitotoxic cell death
Maria M Semenova1,4, Anu M J Mäki-Hokkonen1,4, Jiong Cao1,4, Vladislav Komarovski1, K Marjut Forsberg1, Milla Koistinaho1,2, Eleanor T Coffey3 & Michael J Courtney1,3
Abstract
Excitotoxic neuronal death contributes to many neurological disorders, and involves calcium influx and stress-activated protein kinases (SAPKs) such as p38
. There is indirect evidence that the small Rho-family GTPases Rac and cdc42 are involved in neuronal death subsequent to the withdrawal of nerve growth factor (NGF), whereas Rho is involved in the inhibition of neurite regeneration and the release of the amyloidogenic A
42 peptide. Here we show that Rho is activated in rat neurons by conditions that elevate intracellular calcium and in the mouse cerebral cortex during ischemia. Rho is required for the rapid glutamate-induced activation of p38 and ensuing neuronal death. The ability of RhoA to activate p38 was not expected, and it was specific to primary neuronal cultures. The expression of active RhoA alone not only activated p38 but also induced neuronal death that was sensitive to the anti-apoptotic protein Bcl-2, showing that RhoA was sufficient to induce the excitotoxic pathway. Therefore, Rho is an essential component of the excitotoxic cell death pathway.
- Department of Neurobiology, A.I. Virtanen Institute, University of Kuopio, Kuopio FIN 70211, Finland.
- Medeia Therapeutics Ltd, Microkatu 1, FI-70211 Kuopio, Finland.
- Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, Turku FIN-20521, Finland.
- These authors contributed equally to this work.
Correspondence to: Michael J Courtney1,3 e-mail: courtney@messi.uku.fi
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