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: Jong-Sung Park, Silvia Manzanero, Jae-Woong Chang, Yuri Choi, Sang-Ha Baik, Yi-Lin Cheng, Yu-I Li, A-Ryeong Gwon, Ha-Na Woo, Jiyeon Jang, In-Young Choi, Joo-Yong Lee, Yong-Keun Jung, Sung-Chun Tang, Christopher G Sobey, Thiruma V Arumugam, Dong-Gyu Jo
• Journal: Brain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 23 Issue 4 Pg. 402-12 (Jul 2013) ISSN: 1750-3639 [Electronic] Switzerland
• PMID: 23211047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 International Society of Neuropathology.

Chemical References

• Kv Channel-Interacting Proteins
• Presenilins
• Glucose

Topics

• Animals
• Animals, Newborn
• Apoptosis (physiology)
• Brain (cytology)
• Brain Ischemia (pathology)
• Cells, Cultured
• Disease Models, Animal
• Embryo, Mammalian
• Glucose (deficiency)
• Hypoxia (pathology)
• Infarction, Middle Cerebral Artery (pathology)
• Kv Channel-Interacting Proteins (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Neurons (metabolism, pathology)
• Presenilins (metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (physiology)
• Time Factors
• Up-Regulation (physiology)