title: Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain.
abstract: 17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3β (GSK3β)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3β, E2 modulates interaction of PELP1 with GSK3β, and PELP1 is a novel substrate for GSK3β. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/β-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX 78229;
authors.forename: Gangadhara R
authors.initials: GR
authors.lastname: Sareddy
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors.forename: Quanguang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Neurobiology Institute of Medical Research Center, North China University of Science and Technology, Tangshan, People's Republic of China 063000;
authors.forename: Ruimin
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors.forename: Erin
authors.initials: E
authors.lastname: Scott
authors.affiliation: Department of Epidemiology & Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229;
authors.forename: Yi
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229; South Texas Veterans Health System, Audie L. Murphy VA Hospital, San Antonio, TX 78229;
authors.forename: Jason C
authors.initials: JC
authors.lastname: O'Connor
authors.affiliation: Department of Epidemiology & Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229;
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX 78229; dbrann@gru.edu vadlamudi@uthscsa.edu.
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30904 dbrann@gru.edu vadlamudi@uthscsa.edu.
authors.forename: Darrell
authors.initials: D
authors.lastname: Brann
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D003071:Cognition; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000378:metabolism*; D007249:Inflammation; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000066829:Neuroprotection / Q000235:genetics*; D016376:Oligonucleotides, Antisense; D010766:Phosphorylation; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C086187:Hmx3 protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: 17-β estradiol; PELP1; cognition; extranuclear; neuroprotection