title: Pin1 promotes neuronal death in stroke by stabilizing Notch intracellular domain.
abstract: OBJECTIVE
  Stroke is a leading cause of mortality and disability. The peptidyl-prolyl cis/trans isomerase Pin1 regulates factors involved in cell growth. Recent evidence has shown that Pin1 plays a major role in apoptosis. However, the role of Pin1 in ischemic stroke remains to be investigated.
  
  
  METHODS
  We used Pin1 overexpression and knockdown to manipulate Pin1 expression and explore the effects of Pin1 in cell death on ischemic stress in vitro and in a mouse stroke model. We also used Pin 1 inhibitor, γ-secretase inhibitor, Notch1 intracellular domain (NICD1)-deleted mutant cells, and Pin1 mutant cells to investigate the underlying mechanisms of Pin1-NICD1-mediated cell death.
  
  
  RESULTS
  Our findings indicate that Pin1 facilitates NICD1 stability and its proapoptotic function following ischemic stroke. Thus, overexpression of Pin1 increased NICD1 levels and enhanced its potentiation of neuronal death in simulated ischemia. By contrast, depletion or knockout of Pin1 reduced the NICD1 level, which in turn desensitized neurons to ischemic conditions. Pin1 interacted with NICD1 and increased its stability by inhibiting FBW7-induced polyubiquitination. We also demonstrate that Pin1 and NICD1 levels increase following stroke. Pin1 heterozygous (+/-) and knockout (-/-) mice, and also wild-type mice treated with an inhibitor of Pin1, each showed reduced brain damage and improved functional outcomes in a model of focal ischemic stroke.
  
  
  CONCLUSIONS
  These results suggest that Pin1 contributes to the pathogenesis of ischemic stroke by promoting Notch signaling, and that inhibition of Pin1 is a novel approach for treating ischemic stroke.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Sang-Ha
authors.initials: SH
authors.lastname: Baik
authors.forename: Mitchell
authors.initials: M
authors.lastname: Fane
authors.forename: Joon Hyung
authors.initials: JH
authors.lastname: Park
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.forename: David
authors.initials: D
authors.lastname: Yang-Wei Fann
authors.forename: Ui Jeong
authors.initials: UJ
authors.lastname: Yun
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Bing Han
authors.initials: BH
authors.lastname: Chai
authors.forename: Jin Su
authors.initials: JS
authors.lastname: Park
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Back
authors.forename: Jae In
authors.initials: JI
authors.lastname: Jeong
authors.forename: Ye Jin
authors.initials: YJ
authors.lastname: Jang
authors.forename: Gahee
authors.initials: G
authors.lastname: Bahn
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Yu-I
authors.initials: YI
authors.lastname: Li
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
authors.forename: Hong Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D017434:Protein Structure, Tertiary / Q000502:physiology; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases; D019696:Peptidylprolyl Isomerase