期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：38
页码：13960-13965
DOI：10.1073/pnas.1413644111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNeuronal necrosis widely occurs in devastating neurodegenerative diseases, such as stroke, traumatic brain injury, and Alzheimer's disease. However, it has long been considered a stochastic process lacking genetic regulations. Our inadequate understanding of its molecular mechanism has hindered pharmacological design to suppress this type of cell death. Through construction and studying of a Drosophila model of neuronal necrosis, we identified a chromatin-modifying cascade to play a key role in execution of neuronal necrosis. Our results indicate that neuronal necrosis is a stereotypically regulated process in both insect and mammalian neurons. This discovery provides previously unidentified biomarkers and potential therapeutic targets for neuronal necrosis. Neuronal necrosis induced by calcium overload causes devastating brain dysfunction in diseases such as stroke and brain trauma. It has been considered a stochastic event lacking genetic regulation, and pharmacological means to suppress neuronal necrosis are lacking. Using a Drosophila model of calcium overloading, we found JIL-1/mitogen- and stress-activated protein kinase 1/2 is a regulator of neuronal necrosis through phosphorylation of histone H3 serine 28 (H3S28ph). Further, we identified its downstream events including displacement of polycomb repressive complex 1 (PRC1) and activation of Trithorax (Trx). To test the role of JIL-1/PRC1/Trx cascade in mammals, we studied the necrosis induced by glutamate in rat cortical neuron cultures and rodent models of brain ischemia and found the cascade is activated in these conditions and inhibition of the cascade suppresses necrosis in vitro and in vivo. Together, our research demonstrates that neuronal necrosis is regulated by a chromatin-modifying cascade, and this discovery may provide potential therapeutic targets and biomarkers for neuronal necrosis.
