Zhou Zhi Dong, Xie Shao Ping, Sathiyamoorthy Sushmitha, Saw Wuan Ting, Sing Tan Ye, Ng Shin Hui, Chua Heidi Pek Hup, Tang Alyssa Mei Yan, Shaffra Fathima, Li Zeng, Wang Hongyan, Ho Patrick Ghim Hoe, Lai Mitchell Kim Peng, Angeles Dario C, Lim Tit Meng, Tan Eng-King
National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore, Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore, Singapore.
National Neuroscience Institute of Singapore, 11 Jalan Tan Tock Seng, Singapore, Singapore.
Hum Mol Genet. 2015 Nov 15;24(22):6314-30. doi: 10.1093/hmg/ddv340. Epub 2015 Aug 26.
The mutations of F-box protein 7 (FBXO7) gene (T22M, R378G and R498X) are associated with a severe form of autosomal recessive juvenile-onset Parkinson's disease (PD) (PARK 15). Here we demonstrated that wild-type (WT) FBXO7 is a stress response protein and it can play both cytoprotective and neurotoxic roles. The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy. Upon stress, the endogenous WT FBXO7 gets up-regulated, concentrates into mitochondria and forms FBXO7 aggregates in mitochondria. However, FBXO7 mutations aggravate deleterious FBXO7 aggregation in mitochondria. The FBXO7 aggregation and toxicity can be alleviated by Proline, glutathione (GSH) and coenzyme Q10, whereas deleterious FBXO7 aggregation in mitochondria can be aggravated by prohibitin 1 (PHB1), a mitochondrial protease inhibitor. The overexpression of WT FBXO7 could lead to FBXO7 protein aggregation and dopamine neuron degeneration in transgenic Drosophila heads. The elevated FBXO7 expression and aggregation were identified in human fibroblast cells from PD patients. FBXO7 can also form aggregates in brains of PD and Alzheimer's disease. Our study provides novel pathophysiologic insights and suggests that FBXO7 may be a potential therapeutic target in FBXO7-linked neuron degeneration in PD.
F-box蛋白7（FBXO7）基因的突变（T22M、R378G和R498X）与一种严重的常染色体隐性青少年型帕金森病（PD）（PARK 15）相关。在此，我们证明野生型（WT）FBXO7是一种应激反应蛋白，它既能发挥细胞保护作用，也能发挥神经毒性作用。WT FBXO7蛋白对细胞线粒体自噬至关重要，可促进线粒体自噬以保护细胞，而突变型FBXO7则抑制线粒体自噬。在应激状态下，内源性WT FBXO7会上调，聚集在线粒体中并在线粒体中形成FBXO7聚集体。然而，FBXO7突变会加剧线粒体中有害的FBXO7聚集。脯氨酸、谷胱甘肽（GSH）和辅酶Q10可减轻FBXO7的聚集和毒性，而线粒体蛋白酶抑制剂 prohibitin 1（PHB1）则会加剧线粒体中有害的FBXO7聚集。WT FBXO7的过表达可导致转基因果蝇头部出现FBXO7蛋白聚集和多巴胺神经元变性。在PD患者的人成纤维细胞中发现FBXO7表达和聚集升高。FBXO7也可在PD和阿尔茨海默病患者的大脑中形成聚集体。我们的研究提供了新的病理生理学见解，并表明FBXO7可能是PD中与FBXO7相关的神经元变性的潜在治疗靶点。
