The endoplasmic reticulum stress sensor, ATF6α, protects against neurotoxin-induced dopaminergic neuronal death.
Oxidative stress and endoplasmic reticulum (ER) stress are thought to contribute to the pathogenesis of various neurodegenerative diseases including Parkinson disease (PD), however, the relationship between these stresses remains unclear. ATF6α is an ER-membrane-bound transcription factor that is activated by protein misfolding in the ER and functions as a critical regulator of ER quality control proteins in mammalian cells. The goal of this study was to explore the cause-effect relationship between oxidative stress and ER stress in the pathogenesis of neurotoxin-induced model of PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin known to produce oxidative stress, activated ATF6α and increased ER chaperones and ER-associated degradation (ERAD) component in dopaminergic neurons. Importantly, MPTP induced formation of ubiquitin- immunopositive inclusions and loss of dopaminergic neurons more prominently in mice deficient in ATF6α than in wild-type mice. Cultured cell experiments revealed that 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress not only promoted phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) but also enhanced interaction between phosphorylated p38MAPK and ATF6α, leading to increment in transcriptional activator activity of ATF6α. Thus, our results revealed a link between oxidative stress and ER stress by showing the importance of ATF6α in the protection of the dopaminergic neurons from MPTP that occurs through oxidative stress-induced activation of ATF6α and p38MAPK-mediated enhancement of ATF6α transcriptional activity.
From the Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan,; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Japan.
Naohiro
N
Egawa
the Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan,; the Institute of Genome Research, Tokushima University, Tokushima 770-8503, Japan.
Keisuke
K
Yamamoto
the Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan, and.
Haruhisa
H
Inoue
From the Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan,; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Japan.
Rie
R
Hikawa
the Tokyo Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan.
Katsunori
K
Nishi
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Japan,; the Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
Kazutoshi
K
Mori
From the Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan,; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Japan,. Electronic address: ryosuket@kuhp.kyoto-u.ac.jp.
Ryosuke
R
Takahashi
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048051:p38 Mitogen-Activated Protein Kinases