Protective effect against Parkinson's disease-related insults through the activation of XBP1.
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.
Sado
Megumi
M
Second Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
Yamasaki
Yuki
Y
Iwanaga
Tomoyuki
T
Onaka
Yasushi
Y
Ibuki
Tatsuki
T
Nishihara
Shigeki
S
Mizuguchi
Hiroshi
H
Momota
Hiroshi
H
Kishibuchi
Ryuichi
R
Hashimoto
Tetsuya
T
Wada
Daisuke
D
Kitagawa
Hisashi
H
Watanabe
Takeshi K
TK
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
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