mRNA Redistribution during Permanent Focal Cerebral Ischemia
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ORIGINAL ARTICLE
mRNA Redistribution during Permanent Focal Cerebral Ischemia Monique K. Lewis & Jill T. Jamison & Joseph C. Dunbar & Donald J. DeGracia
Received: 20 May 2013 / Revised: 18 July 2013 / Accepted: 19 July 2013 / Published online: 6 August 2013 # Springer Science+Business Media New York 2013
Abstract Translation arrest occurs in neurons following focal cerebral ischemia and is irreversible in penumbral neurons destined to die. Following global cerebral ischemia, mRNA is sequestered away from 40S ribosomal subunits as mRNA granules, precluding translation. Here, we investigated mRNA granule formation using fluorescence in situ histochemistry out to 8 h permanent focal cerebral ischemia using middle cerebral artery occlusion in Long Evans rats with and without diabetes. Neuronal mRNA granules colocalized with PABP, HuR, and NeuN, but not 40S or 60S ribosomal subunits, or organelle markers. The volume of brain with mRNA granule-containing neurons decreased exponentially with ischemia duration, and was zero after 8 h permanent focal cerebral ischemia or any duration of ischemia in diabetic rats. These results show that neuronal mRNA granule response has a limited range of insult intensity over which it is expressed. Identifying the limits of effective neuronal stress response to ischemia will be important for developing effective stroke therapies. Keywords Focal cerebral ischemia . HSP70 . HuR . Middle cerebral artery occlusion . mRNA granules . Protein synthesis inhibition . Stress granules . Translation arrest Electronic supplementary material The online version of this article (doi:10.1007/s12975-013-0274-1) contains supplementary material, which is available to authorized users. M. K. Lewis : J. T. Jamison : J. C. Dunbar : D. J. DeGracia (*) Department of Physiology, Wayne State University School of Medicine, 4116 Scott Hall, 540 East Canfield Ave Detroit, MI 48201, USA e-mail: [email protected] D. J. DeGracia Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Abbreviations CA Cornu Ammonis CCA Common carotid artery COX IV Cytochrome c oxidase subunit IV DND Delayed neuronal death eIF2 Eukaryotic initiation factor-2 ER Endoplasmic reticulum FISH Fluorescent in situ hybridization GM130 cis-Golgi matrix marker 130 kDa IF Immunofluorescence histochemistry IP Intraperitoneal I/R Ischemia and reperfusion LONI Laboratory of Neuroimaging at University of California Los Angeles MCA Middle cerebral artery MCAO Middle cerebral artery occlusion NeuN Neuronal nuclei NF H/M Neurofilament heavy and medium weight chains pA Polyadenylated mRNAs PABP Polyadenylated mRNA-binding protein PDI Protein disulfide isomerase pMCAO Permanent MCAO RPA Ribosomal P antigen SG Stress granules S6 Constituent protein of the 40S small ribosomal subunit STZ Streptozocin TA Translation arrest TGN38 trans-Golgi network 38 kDa antigen TIA-1 T-cell internal antigen TTC 2,3,5-Triphenyltetrazolium chloride TTP Tristetraprolin
Transl. Stroke Res. (2013) 4:604–617
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