A master regulatory network restoring brain glutamate homeostasis is coordinately activated in stroke

Somewhere in these 29 pages something might be useful. Which our great stroke association would analyze and distribute worldwide. Because right now your doctor and stroke hospital are not updating their stroke recovery protocols at all. https://www.biorxiv.org/content/biorxiv/early/2018/01/10/245928.full.pdf Mariko Kobayashi1,3, Corey Anderson2, Corinne Benakis2, Michael J. Moore1, Aldo Mele1, John J. Fak1, Christopher Y. Park1, Ping Zhou2, Josef Anrather2, Costantino Iadecola2, Robert B. Darnell1,3. 1Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. 2Fell Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA. 3Correspondence: mkobayashi@rockefeller.edu, darnelr@rockefeller.edu
ABSTRACT
Altered miRNA expression in various disease states have been identified, but their global targets contributing to the collective regulatory power to promote or attenuate pathology remains poorly defined. Here we applied a combination of hi-throughput RNA profiling techniques, including AGO CLIP, miRNAseq, RNAseq and ribosomal profiling, to develop an unbiased and comprehensive view of miRNA:mRNA functional interactions following ischemia/reperfusion (IR) injury in the mouse brain. Upon acute I/R insult miR-29 family members were most prominently lost, with corresponding de-regulation of their global target sites. This leads to a dynamic, cascading mode of miR-29 target transcript activation, orchestrated by an initial translational activation and subsequent increase in target mRNA levels. Unexpectedly, activated genes include factors essential for glutamate signaling and reuptake, indicating a fundamental role for this regulatory network in modulating criticalendogenous neuroprotective programs to restore brain homeostasis. We integrated this data with human brain AGO CLIP profiles to infer target site variants that determine miRNA binding and to explore the role of non-coding site polymorphisms in stroke. Together these results establish a new strategy for understanding RNA regulatory networks in complex neurological disease.