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. ATF6␣ 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 ATF6␣ 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 ATF6␣ 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 ATF6␣, leading to increment in transcriptional activator activity of ATF6␣. Thus, our results revealed a link between oxidative stress and ER stress by showing the importance of ATF6␣ in the protection of the dopaminergic neurons from MPTP that occurs through oxidative stress-induced activation of ATF6␣ and p38MAPK-mediated enhancement of ATF6␣ transcriptional activity.

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