Kano Masayoshi, Takanashi Masashi, Oyama Genko, Yoritaka Asako, Hatano Taku, Shiba-Fukushima Kahori, Nagai Makiko, Nishiyama Kazutoshi, Hasegawa Kazuko, Inoshita Tsuyoshi, Ishikawa Kei-Ichi, Akamatsu Wado, Imai Yuzuru, Bolognin Silvia, Schwamborn Jens Christian, Hattori Nobutaka
Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo, 113-8421, Japan.
Department of Neurology, Juntendo Koshigaya Hospital, 560 Fukuroyama, Koshigaya, Saitama, 343-0032, Japan.
NPJ Parkinsons Dis. 2020 Nov 13;6(1):33. doi: 10.1038/s41531-020-00137-8.
Parkin (encoded by PRKN) is a ubiquitin ligase that plays an important role in cellular mitochondrial quality control. Mutations in PRKN cause selective dopaminergic cell loss in the substantia nigra and are presumed to induce a decrease in mitochondrial function caused by the defective clearance of mitochondria. Several studies have demonstrated that parkin dysfunction causes mitochondrial injury and astrocytic dysfunction. Using immunohistochemical methods, we analyzed astrocytic changes in human brains from individuals with PRKN mutations. Few glial fibrillary acidic protein- and vimentin-positive astrocytes were observed in the substantia nigra in PRKN-mutated subjects compared with subjects with idiopathic Parkinson's disease. We also differentiated patient-specific induced pluripotent stem cells into midbrain organoids and confirmed decreased numbers of glial fibrillary acidic protein-positive astrocytes in PRKN-mutated organoids compared with age- and sex-matched controls. Our study reveals PRKN-mutation-induced astrocytic alteration and suggests the possibility of an astrocyte-related non-autonomous cell death mechanism for dopaminergic neurons in brains of PRKN-mutated patients.
帕金蛋白（由PRKN基因编码）是一种泛素连接酶，在细胞线粒体质量控制中发挥重要作用。PRKN基因突变会导致黑质中多巴胺能细胞选择性缺失，据推测会因线粒体清除缺陷而导致线粒体功能下降。多项研究表明，帕金蛋白功能障碍会导致线粒体损伤和星形胶质细胞功能障碍。我们采用免疫组织化学方法，分析了携带PRKN基因突变个体的人脑星形胶质细胞变化。与特发性帕金森病患者相比，PRKN基因突变患者黑质中很少观察到胶质纤维酸性蛋白和波形蛋白阳性的星形胶质细胞。我们还将患者特异性诱导多能干细胞分化为中脑类器官，并证实与年龄和性别匹配的对照组相比，PRKN基因突变类器官中胶质纤维酸性蛋白阳性星形胶质细胞数量减少。我们的研究揭示了PRKN基因突变诱导的星形胶质细胞改变，并提示PRKN基因突变患者大脑中多巴胺能神经元可能存在与星形胶质细胞相关的非自主性细胞死亡机制。
