The Endoplasmic Reticulum Stress Sensor, ATF6α, Protects against Neurotoxin-induced Dopaminergic Neuronal Death

Abstract

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.

Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

“…It has been reported by Silva et al [115], that deficiency of CHOP, a key ER stress marker, protects the neonatal striatum from neurotoxicant 6-hydroxydopamine. Reports also showed that forced expression of ER stress sensor proteins, ATF6 alpha [117] and spliced XBP1 [116], confines neurotoxininduced dopaminergic neuronal death [117]. These reports are indicative of the role of ER stress in the death and dysfunction of dopaminergic neurons exposed to neurotoxicant models of PD.…”

ER Stress and Disease: Toward Prevention and Treatment

“…9) In addition, drugs which induce PD, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), cause ER stress, and the involvement of ATF6 activation in this process has been reported. 31) While nitric oxide (NO) is known to induce ER stress, protein-disulfide isomerase (PDI) that works on protein disulfide bond formation in the ER has been identified as a NO target. When cysteine residues in the PDI enzyme active sites are Snitrosylated by NO, the enzyme activity declines, resulting in the accumulation of defective proteins in the ER.…”

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

“…This observation was also confirmed in a model where XBP1 is delivered to neuronal stem cells transferred to animals treated with rotenone [90]. ATF6 deficient animals exhibit increased ubiquitin positive inclusions and exacerbated dopaminergic neuron loss following MPTP treatment [91,92]. Overexpression of BiP using a gene therapy strategy also proved to be neuroprotective for dopaminergic neurons after overexpression of human α-synuclein in rats [93].…”