Neuronal Rho GTPase Rac1 elimination confers neuroprotection in a mouse model of permanent ischemic stroke
Abstract
Abstract The Rho GTPase Rac1 is a multifunctional protein involved in distinct pathways ranging from development to pathology. The aim of the present study was to unravel the contribution of neuronal Rac1 in regulating the response to brain injury induced by permanent focal cerebral ischemia (pMCAO). Our results show that pMCAO significantly increased total Rac1 levels in wild type mice, mainly through rising nuclear Rac1, while a reduction in Rac1 activation was observed. Such changes preceded cell death induced by excitotoxic stress. Pharmacological inhibition of Rac1 in primary neuronal cortical cells prevented the increase in oxidative stress induced after overactivation of glutamate receptors. However, this was not sufficient to prevent the associated neuronal cell death. In contrast, RNAi‐mediated knock down of Rac1 in primary cortical neurons prevented cell death elicited by glutamate excitotoxicity and decreased the activity of NADPH oxidase. To test whether in vivo down regulation of neuronal Rac1 was neuroprotective after pMCAO, we used tamoxifen‐inducible neuron‐specific conditional Rac1‐knockout mice. We observed a significant 50% decrease in brain infarct volume of knockout mice and a concomitant increase in HIF‐1α expression compared to littermate control mice, demonstrating that ablation of Rac1 in neurons is neuroprotective. Transmission electron microscopy performed inmore »
- Authors:
-
- i3S – Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal, Glial Cell Biology IBMC‐ Instituto de Biologia Molecular e Celular, Universidade do Porto Porto Portugal, Department of Neurobiology Research, Institute of Molecular Medicine University of Southern Denmark Odense C Denmark
- i3S – Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal, HEMS, IBMC‐Instituto de Biologia Molecular e Celular, Universidade do Porto Porto Portugal
- i3S – Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal, Glial Cell Biology IBMC‐ Instituto de Biologia Molecular e Celular, Universidade do Porto Porto Portugal
- Biotech Research and Innovation Center University of Copenhagen Denmark
- Department of Neurobiology Research, Institute of Molecular Medicine University of Southern Denmark Odense C Denmark, Department of Neurology Odense University Hospital Odence C Denmark, BRIDGE – Brain Research – Inter‐Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense Denmark
- i3S – Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal, Glial Cell Biology IBMC‐ Instituto de Biologia Molecular e Celular, Universidade do Porto Porto Portugal, INEB – Instituto de Engenharia Biomédica, Universidade do Porto, Porto Portugal.
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1404731
- Resource Type:
- Publisher's Accepted Manuscript
- Journal Name:
- Brain Pathology
- Additional Journal Information:
- Journal Name: Brain Pathology Journal Volume: 28 Journal Issue: 4; Journal ID: ISSN 1015-6305
- Publisher:
- Wiley-Blackwell
- Country of Publication:
- Country unknown/Code not available
- Language:
- English
Citation Formats
Karabiyik, Cansu, Fernandes, Rui, Figueiredo, Francisco Rosário, Socodato, Renato, Brakebusch, Cord, Lambertsen, Kate Lykke, Relvas, João Bettencourt, and Santos, Sofia Duque. Neuronal Rho GTPase Rac1 elimination confers neuroprotection in a mouse model of permanent ischemic stroke. Country unknown/Code not available: N. p., 2017.
Web. doi:10.1111/bpa.12562.
Karabiyik, Cansu, Fernandes, Rui, Figueiredo, Francisco Rosário, Socodato, Renato, Brakebusch, Cord, Lambertsen, Kate Lykke, Relvas, João Bettencourt, & Santos, Sofia Duque. Neuronal Rho GTPase Rac1 elimination confers neuroprotection in a mouse model of permanent ischemic stroke. Country unknown/Code not available. https://doi.org/10.1111/bpa.12562
Karabiyik, Cansu, Fernandes, Rui, Figueiredo, Francisco Rosário, Socodato, Renato, Brakebusch, Cord, Lambertsen, Kate Lykke, Relvas, João Bettencourt, and Santos, Sofia Duque. Tue .
"Neuronal Rho GTPase Rac1 elimination confers neuroprotection in a mouse model of permanent ischemic stroke". Country unknown/Code not available. https://doi.org/10.1111/bpa.12562.
@article{osti_1404731,
title = {Neuronal Rho GTPase Rac1 elimination confers neuroprotection in a mouse model of permanent ischemic stroke},
author = {Karabiyik, Cansu and Fernandes, Rui and Figueiredo, Francisco Rosário and Socodato, Renato and Brakebusch, Cord and Lambertsen, Kate Lykke and Relvas, João Bettencourt and Santos, Sofia Duque},
abstractNote = {Abstract The Rho GTPase Rac1 is a multifunctional protein involved in distinct pathways ranging from development to pathology. The aim of the present study was to unravel the contribution of neuronal Rac1 in regulating the response to brain injury induced by permanent focal cerebral ischemia (pMCAO). Our results show that pMCAO significantly increased total Rac1 levels in wild type mice, mainly through rising nuclear Rac1, while a reduction in Rac1 activation was observed. Such changes preceded cell death induced by excitotoxic stress. Pharmacological inhibition of Rac1 in primary neuronal cortical cells prevented the increase in oxidative stress induced after overactivation of glutamate receptors. However, this was not sufficient to prevent the associated neuronal cell death. In contrast, RNAi‐mediated knock down of Rac1 in primary cortical neurons prevented cell death elicited by glutamate excitotoxicity and decreased the activity of NADPH oxidase. To test whether in vivo down regulation of neuronal Rac1 was neuroprotective after pMCAO, we used tamoxifen‐inducible neuron‐specific conditional Rac1‐knockout mice. We observed a significant 50% decrease in brain infarct volume of knockout mice and a concomitant increase in HIF‐1α expression compared to littermate control mice, demonstrating that ablation of Rac1 in neurons is neuroprotective. Transmission electron microscopy performed in the ischemic brain showed that lysosomes in the infarct of Rac1‐ knockout mice were preserved at similar levels to those of non‐infarcted tissue, while littermate mice displayed a decrease in the number of lysosomes, further corroborating the notion that Rac1 ablation in neurons is neuroprotective. Our results demonstrate that Rac1 plays important roles in the ischemic pathological cascade and that modulation of its levels is of therapeutic interest.},
doi = {10.1111/bpa.12562},
journal = {Brain Pathology},
number = 4,
volume = 28,
place = {Country unknown/Code not available},
year = {Tue Oct 24 00:00:00 EDT 2017},
month = {Tue Oct 24 00:00:00 EDT 2017}
}
https://doi.org/10.1111/bpa.12562
Web of Science
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