A1 Refereed original research article in a scientific journal
Rho mediates calcium-dependent activation of p38 alpha and subsequent excitotoxic cell death
Authors: Semenova MM, Maki-Hokkonen AMJ, Cao J, Komarovski V, Forsberg KM, Koistinaho M, Coffey ET, Courtney MJ
Publisher: NATURE PUBLISHING GROUP
Publication year: 2007
Journal: Nature Neuroscience
Journal name in source: NATURE NEUROSCIENCE
Journal acronym: NAT NEUROSCI
Volume: 10
Issue: 4
First page : 436
Last page: 443
Number of pages: 8
ISSN: 1097-6256
DOI: https://doi.org/10.1038/nn1869
Self-archived copy’s web address: http://research.utu.fi/converis/portal/Publication/18499886
Excitotoxic neuronal death contributes to many neurological disorders, and involves calcium influx and stress-activated protein kinases (SAPKs) such as p38 alpha. 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 beta(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 p38a and ensuing neuronal death. The ability of RhoA to activate p38 alpha was not expected, and it was specific to primary neuronal cultures. The expression of active RhoA alone not only activated p38 alpha 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.
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