title: Neuroprotective Effects of Protein Tyrosine Phosphatase 1B Inhibition against ER Stress-Induced Toxicity.
abstract: Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers (eIF2α phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene inDrosophilamitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases.
authors.affiliation: Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 41068, Korea.
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Jeon
authors.affiliation: Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 41068, Korea.
authors.forename: Shinrye
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 41068, Korea.
authors.forename: Seyeon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 41068, Korea.
authors.forename: Younghwi
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Department of Medical Biotechnology, Soonchunhyang University, Asan 31538, Korea.
authors.forename: Kiyoung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea.
authors.forename: Chang Geon
authors.initials: CG
authors.lastname: Chung
authors.affiliation: Gwangju Center, Korea Basic Science Institute (KBSI), Gwangju 61186, Korea.
authors.forename: Seongsoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Brain & Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea.
authors.forename: Sung Bae
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 41068, Korea.
authors.forename: Hyung-Jun
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D016923:Cell Death; D002540:Cerebral Cortex / Q000201:enzymology; D015536:Down-Regulation; D004330:Drosophila / Q000201:enzymology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D019636:Neurodegenerative Diseases / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D000066829:Neuroprotection; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000187:drug effects
chemical_list: D015852:Eukaryotic Initiation Factor-2; D007976:Leupeptins; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017382:Reactive Oxygen Species; D012402:Rotenone; D014475:Uncoupling Agents; D019892:eIF-2 Kinase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: MG132; endoplasmic reticulum stress (ER Stress); reactive oxygen species (ROS); rotenone; ubiquitin proteasome system