title: Protective effect against Parkinson's disease-related insults through the activation of XBP1.
abstract: The accumulation of misfolded and unfolded proteins in endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). Recent evidence has suggested the relationship between UPR and dopaminergic neuronal cell death in Parkinson's disease (PD); however, it remains unclear whether it makes sense to modulate UPR, to mitigate the progression of PD. In this study, we investigated a role of the IRE1 alpha-XBP1 pathway in the survival of dopaminergic cells, under stress induced by PD-related insults. The exogenous expression of the active-form XBP1 (XBP1s) protein had protective effects against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and proteasome inhibitors. Moreover, adenoviral XBP1s expression significantly suppressed the degeneration of dopaminergic neurons in the mouse model of PD, as induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results demonstrate that the enhancement of XBP1 could be a novel PD therapeutic strategy.
authors.affiliation: Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Sado
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Iwanaga
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Onaka
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Ibuki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nishihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Momota
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kishibuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Wada
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Takeshi K
authors.initials: TK
authors.lastname: Watanabe
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000502:physiology; D004722:Endoribonucleases / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D007976:Leupeptins; D008565:Membrane Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C067713:lactacystin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D015655:1-Methyl-4-phenylpyridinium; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine; D000111:Acetylcysteine