title: Geldanamycin attenuates 3‑nitropropionic acid‑induced apoptosis and JNK activation through the expression of HSP 70 in striatal cells.
abstract: Although selective striatal cell death is a characteristic hallmark in the pathogenesis of Huntington's disease (HD), the underlying mechanism of striatal susceptibility remains to be clarified. Heat shock proteins (HSPs) have been reported to suppress the aggregate formation of mutant huntingtin and concurrent striatal cell death. In a previous study, we observed that heat shock transcription factor 1 (HSF1), a major transcription factor of HSPs, significantly attenuated 3‑nitropropionic acid (3NP)‑induced reactive oxygen species (ROS) production and apoptosis through the expression of HSP 70 in striatal cells. To investigate the differential roles of HSPs in 3NP‑induced striatal cell death, the effect of geldanamycin (GA), an HSP 90 inhibitor, was examined in 3NP‑stimulated striatal cells. GA significantly attenuated 3NP‑induced striatal apoptosis and ROS production with an increased expression of HSP 70. Triptolide (TL), an HSP 70 inhibitor, abolished GA‑mediated protective effects in 3NP‑stimulated striatal cells. To understand the underlying mechanism by which GA‑mediated HSP 70 protects striatal cells against 3NP stimulation, the involvement of various signaling pathways was examined. GA significantly attenuated 3NP‑induced c‑Jun N‑terminal kinase (JNK) phosphorylation and subsequent c‑Jun phosphorylation in striatal cells. Taken together, the present study demonstrated that GA exhibits protective properties against 3NP‑induced apoptosis and JNK activation via the induction of HSP 70 in striatal cells, suggesting that expression of HSP 70 may be a valuable therapeutic target in the treatment of HD.
authors.affiliation: Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Gangwon 200‑701, Republic of Korea.
authors.forename: Yong-Joon
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Gangwon 200‑701, Republic of Korea.
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Gangwon 200‑701, Republic of Korea.
authors.forename: Man Sup
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Gangwon 200‑701, Republic of Korea.
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Gangwon 200‑701, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Gangwon 200‑701, Republic of Korea.
authors.forename: Wanjoo
authors.initials: W
authors.lastname: Chun
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016227:Benzoquinones; D004224:Diterpenes; D004852:Epoxy Compounds; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009574:Nitro Compounds; D010616:Phenanthrenes; D011422:Propionates; D017382:Reactive Oxygen Species; C001899:triptolide; D048031:JNK Mitogen-Activated Protein Kinases; C015392:3-nitropropionic acid; C001277:geldanamycin
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