| First Author | Hashida K | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 10 | Pages | e47950 |
| PubMed ID | 23112876 | Mgi Jnum | J:192297 |
| Mgi Id | MGI:5464267 | Doi | 10.1371/journal.pone.0047950 |
| Citation | Hashida K, et al. (2012) ATF6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson's disease. PLoS One 7(10):e47950 |
| abstractText | 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 ATF6alpha and PERK/eIF2alpha/ATF4, was observed after MPTP/P injections into mice. Deletion of the ATF6alpha 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 ATF6alpha -/- mice after MPTP/P injections. Decreased BDNF expression in ATF6alpha -/- mice was associated with decreased expression of GRP78, an ATF6alpha-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. |
