Affordable Access

Publisher Website

Salubrinal protects against rotenone-induced SH-SY5Y cell death via ATF4-parkin pathway

Authors
Journal
Brain Research
0006-8993
Publisher
Elsevier
Publication Date
Volume
1549
Identifiers
DOI: 10.1016/j.brainres.2014.01.003
Keywords
  • Salubrinal
  • Rotenone
  • Er Stress
  • Atf4
  • Parkin
Disciplines
  • Biology
  • Medicine
  • Pharmacology

Abstract

Abstract Parkinson's disease (PD) is a progressive neurodegenerative disorder, for which there are no effective disease-modifying therapies. Growing evidence from studies in human PD brain, in addition to genetic and toxicological models, indicates that endoplasmic reticulum (ER) stress is a common feature of the disease and contributes to neurodegeneration. We examine whether salubrinal, a ER stress inhibitor, can protect the rotenone-induced SH-SY5Y cell death and explore the mechanisms underlying this protection. Our results demonstrated that rotenone induced a significant ER stress response and caused cell apoptosis, which was inhibited by salubrinal. Activating transcription factor 4 (ATF4), a member of the ATF/CREB family of basic leucine zipper transcription factors, has been implicated in the pathogenesis of neurodegeneration. We showed that salubrinal increased the up-regulation of ATF4 expression. An ATF4 siRNA significantly increased the rotenone cytotoxicity and decreased the salubrinal's protection. Further, we showed that ATF4 siRNA inhibited the expression of parkin, and parkin knockdown similarly aggravated the rotenone cytotoxicity and reduced the salubrinal's protection. Additionally, the protein level of parkin was declined after treatment with rotenone, whereas this reduction was rescued by salubrinal. These findings indicate ATF4-parkin pathway plays an important role in the salubrinal-mediated neuroprotection of rotenone-induced dopaminergic cell death.

There are no comments yet on this publication. Be the first to share your thoughts.