ATPase Thorase Deficiency Causes α-Synucleinopathy and Parkinson’s Disease-like Behavior
Fei Gao,
Han Zhang,
Jia Yang,
Menghua Cai,
Qi Yang,
Huaishan Wang,
Yi Xu,
Hui Chen,
Yu Hu,
Wei He,
Jianmin Zhang
Affiliations
Fei Gao
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Han Zhang
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Jia Yang
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Menghua Cai
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Qi Yang
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Huaishan Wang
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Yi Xu
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Hui Chen
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Yu Hu
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Wei He
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Jianmin Zhang
Department of Immunology, Research Center on Pediatric Development and Diseases, Key Laboratory of T Cell and Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing 100005, China
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases and is pathologically characterized by α-synucleinopathy, which is harmful to dopaminergic neurons. However, the underlying mechanisms and pathogenesis of PD remain unclear. The AAA + ATPase Thorase was identified as being essential for neuroprotection and synaptic plasticity by regulating the AMPA receptor trafficking. Here, we found that conditional knockout of Thorase resulted in motor behaviors indicative of neurodegeneration. Genetic deletion of Thorase exacerbated phenotypes of α-synucleinopathy in a familial PD-like A53T mouse model, whereas overexpression of Thorase prevented α-syn accumulation in vivo. Biochemical and cell cultures studies presented here suggest that Thorase interacts with α-syn and regulates the degradation of ubiquitinated α-syn. Thorase deficiency promotes α-syn aggregation in primary cultured neurons. The discoveries in this study provide us with a further understanding of the pathogenesis of α-synucleinopathies including PD.
