title: Salubrinal protects against rotenone-induced SH-SY5Y cell death via ATF4-parkin pathway.
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.
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China.
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Neurology, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Jiangsu 210029, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Neurology, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Jiangsu 210029, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Neurology, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Jiangsu 210029, PR China.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Shi
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China. Electronic address: tyy9956@163.com.
authors.forename: You-Yong
authors.initials: YY
authors.lastname: Tian
authors.affiliation: Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, PR China. Electronic address: zhangyingdong@aliyun.com.
authors.forename: Ying-Dong
authors.initials: YD
authors.lastname: Zhang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012402:Rotenone / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D002934:Cinnamates; D018696:Neuroprotective Agents; C496827:salubrinal; D012402:Rotenone; D051701:Activating Transcription Factor 4; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D013890:Thiourea
keywords: ATF4; ER stress; Parkin; Rotenone; Salubrinal