title: Calsenilin contributes to neuronal cell death in ischemic stroke.
abstract: Calsenilin is a calcium sensor protein that interacts with presenilin and increases calcium-triggered neuronal apoptosis, and γ-secretase activity. Notch is a cell surface receptor that regulates cell-fate decisions and synaptic plasticity in brain. The aim of the present study was to characterize the role of calsenilin as a regulator of the γ-secretase cleavage of Notch in ischemic stroke. Here, we determined the modulation of expression level and cellular distribution of calsenilin in neurons subjected to ischemic-like conditions. The levels of calsenilin and presenilin were increased in primary neurons after oxygen and glucose deprivation. Furthermore, calsenilin was found to enhance the γ-secretase cleavage of Notch and to contribute to cell death under ischemia-like conditions. The inhibition of γ-secretase activity and a presenilin deficiency were both found to protect against calsenilin-mediated ischemic neuronal death. The expression of calsenilin was found to be increased in brain following experimental ischemic stroke. These findings establish a specific molecular mechanism by which the induction of calsenilin enhances Notch activation in ischemic stroke, and identify calsenilin as an upstream of the γ-secretase cleavage of Notch.
authors.affiliation: The School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Silvia
authors.initials: S
authors.lastname: Manzanero
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Chang
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.forename: Sang-Ha
authors.initials: SH
authors.lastname: Baik
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.forename: Yu-I
authors.initials: YI
authors.lastname: Li
authors.forename: A-Ryeong
authors.initials: AR
authors.lastname: Gwon
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Woo
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Jang
authors.forename: In-Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
authors.forename: Sung-Chun
authors.initials: SC
authors.lastname: Tang
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000166:cytology; D002545:Brain Ischemia / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D053763:Presenilins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
chemical_list: D051605:Kv Channel-Interacting Proteins; D053763:Presenilins; D005947:Glucose