atf6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of parkinson’s diseaseatf6alpha促进astroglial激活和神经元生存在一个慢性帕金森病小鼠模型.pdfVIP

ATF6alpha Promotes Astroglial Activation and Neuronal Survival in a Chronic Mouse Model of Parkinson’s Disease Koji Hashida1,2, Yasuko Kitao1,2, Hirofumi Sudo1,2, Yoshitaka Awa1,2, Shinichiro Maeda1,2, 2,3 2,4 5 1,2 Kazutoshi Mori , Ryosuke Takahashi , Munekazu Iinuma , Osamu Hori * 1 Department of Neuroanatomy, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan, 2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology (JST), Tokyo, Japan, 3 Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan, 4 Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 5 Laboratory of Pharmacognosy, Gifu Pharmaceutical University, Gifu City, Gifu, Japan 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 ATF6a and PERK/eIF2a/ATF4, was observed after MPTP/P injections into mice. Deletion of the ATF6a 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 ATF6a 2/ 2 mice after MPTP/P injections. Decreased BDNF expression in ATF6a 2/ 2 mice was associated with decreased expression of GRP78, a