title: ATF6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson's disease.
abstract: Accumulating evidence suggests a crucial role for the unfolded protein response (UPR) in Parkinson's disease (PD). In this study, we investigated the relevance of the UPR in a mouse model of chronic MPTP/probenecid (MPTP/P) injection, which causes severe and persistent degeneration of dopaminergic neurons. Enhanced activation of the UPR branches, including ATF6α and PERK/eIF2α/ATF4, was observed after MPTP/P injections into mice. Deletion of the ATF6α gene accelerated neuronal degeneration and ubiquitin accumulation relatively early in the MPTP/P injection course. Surprisingly, astroglial activation was strongly suppressed, and production of the brain-derived neurotrophic factor (BDNF) and anti-oxidative genes, such as heme oxygenase-1 (HO-1) and xCT, in astrocytes were reduced in ATF6α -/- mice after MPTP/P injections. Decreased BDNF expression in ATF6α -/- mice was associated with decreased expression of GRP78, an ATF6α-dependent molecular chaperone in the ER. Decreased HO-1 and xCT levels were associated with decreased expression of the ATF4-dependent pro-apoptotic gene CHOP. Consistent with these results, administration of the UPR-activating reagent tangeretin (5,6,7,8,4'-pentamethoxyflavone; IN19) into mice enhanced the expression of UPR-target genes in both dopaminergic neurons and astrocytes, and promoted neuronal survival after MPTP/P injections. These results suggest that the UPR is activated in a mouse model of chronic MPTP/P injection, and contributes to the survival of nigrostriatal dopaminergic neurons, in part, through activated astrocytes.
authors.affiliation: Department of Neuroanatomy, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hashida
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sudo
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Awa
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Maeda
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mori
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D002908:Chronic Disease; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D025801:Ubiquitin