Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Gangadhara R. Sareddy, Quanguang Zhang, Ruimin Wang, Erin Scott, Yi Zou, Jason C. O'Connor, Yidong Chen, Yan Dong, Ratna K. Vadlamudi, Darrell W Brann

Research output: Contribution to journalArticle

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Abstract

17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlyingmechanism 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 FBKOmice, 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.

Original languageEnglish (US)
Pages (from-to)E6673-E6682
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number48
DOIs
StatePublished - Dec 1 2015

Fingerprint

Estrogens
Brain
Glycogen Synthase Kinase 3
Prosencephalon
Brain Ischemia
Knockout Mice
Cognition
Neuroprotection
human PELP1 protein
Hippocampal CA1 Region
Catenins
Wnt Signaling Pathway
Extracellular Signal-Regulated MAP Kinases
Neurodegenerative Diseases
Estradiol
Ischemia
Phosphorylation
RNA
Inflammation
Genes

Keywords

  • 17-β estradiol
  • Cognition
  • Extranuclear
  • Neuroprotection
  • PELP1

ASJC Scopus subject areas

  • General

Cite this

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain. / Sareddy, Gangadhara R.; Zhang, Quanguang; Wang, Ruimin; Scott, Erin; Zou, Yi; O'Connor, Jason C.; Chen, Yidong; Dong, Yan; Vadlamudi, Ratna K.; Brann, Darrell W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 48, 01.12.2015, p. E6673-E6682.

Research output: Contribution to journalArticle

Sareddy, Gangadhara R. ; Zhang, Quanguang ; Wang, Ruimin ; Scott, Erin ; Zou, Yi ; O'Connor, Jason C. ; Chen, Yidong ; Dong, Yan ; Vadlamudi, Ratna K. ; Brann, Darrell W. / Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 48. pp. E6673-E6682.
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AU - Sareddy, Gangadhara R.

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AU - Zou, Yi

AU - O'Connor, Jason C.

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AB - 17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlyingmechanism 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 FBKOmice, 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.

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