The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection

• Published in: Neurobiology of disease Vol. 43; no. 2; pp. 388 - 396
• Main Authors: Chip, Sophorn, Zelmer, Andrea, Ogunshola, Omolara O, Felderhoff-Mueser, Ursula, Nitsch, Cordula, Bührer, Christoph, Wellmann, Sven
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2011; Elsevier
• Subjects: Animals; Animals, Newborn; Apoptosis; Asphyxia; Brain; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebral Cortex - physiology; Encephalopathy; Gene Expression Regulation, Developmental - physiology; Hypothermia, Induced - methods; Hypoxia-ischemia; Infant; Mice; Mice, Inbred C57BL; Neurology; Neuron; Neuronal stem cell; Neuroprotective Agents - antagonists & inhibitors; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Organ Culture Techniques - methods; PC12 Cells; Rats; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - physiology; poly ADP-ribose polymerase; Brain; RNA-binding motif protein 3; RNA-recognition motif; Cortical organotypic slice cultures; Staurosporine; Nerve growth factor; Infant; PARP; RRM; RBM3; External granular cell layer; Neuron-specific nuclear protein; STS; Encephalopathy; Subgranular layer; Rat pheochromocytoma cells; ML; COSCs; Neuronal stem cell; Serum-glucose deprivation; EGL; Asphyxia; NGF; IGL; PC12; SGD; Internal granular cells layer; Neuron; Purkinje cell layer; NeuN; Doublecortin; cold inducible protein; DCX; PCL; SGL; CIRP; Molecular layer; Hypoxia-ischemia; Apoptosis
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2011.04.010

Abstract Induced hypothermia is the only therapy with proven efficacy to reduce brain damage after perinatal asphyxia. While hypothermia down-regulates global protein synthesis and cell metabolism, low temperature induces a small subset of proteins that includes the RNA-binding protein RBM3 (RNA-binding motif protein 3), which has recently been implicated in cell survival. Here, immunohistochemistry of the developing postnatal murine brain revealed a spatio-temporal neuronal RBM3 expression pattern very similar to that of doublecortin, a marker of neuronal precursor cells. Mild hypothermia (32 °C) profoundly promoted RBM3 expression and rescued neuronal cells from forced apoptosis as studied in primary neurons, PC12 cells, and cortical organotypic slice cultures. Blocking RBM3 expression in neuronal cells by specific siRNAs significantly diminished the neuroprotective effect of hypothermia while vector-driven RBM3 over-expression reduced cleavage of PARP, prevented internucleosomal DNA fragmentation, and LDH release also in the absence of hypothermia. Together, neuronal RBM3 up-regulation in response to hypothermia apparently accounts for a substantial proportion of hypothermia-induced neuroprotection.