机构：[a]Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repairing, Beijing Key Laboratory of Brain Major Disorders-State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing,[b]Core Facilities Center, Capital Medical University, Beijing,[c]Department of Physiology, Capital Medical University, Beijing,[d]Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China,首都医科大学附属天坛医院[e]Division of Neurobiology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, USA
Background/Aims: Alpha-synuclein (alpha-Syn) is a neuronal protein that is highly implicated in Parkinson's disease (PD), and protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that is associated with neurodegenerative diseases, such as PD. alpha-Syn can directly upregulate PP2A activity, but the underling mechanism remains unclear. Therefore, we investigated the molecular mechanism of alpha-Syn regulating PP2A activity. Methods: alpha-Syn and its truncations were expressed in E. coli, and purified by affinity chromatography. PP2A C alpha and its mutants were expressed in recombinant baculovirus, and purified by affinity chromatography combined with gel filtration chromatography. The interaction between alpha-Syn and PP2A C alpha was detected by GST pull-down assay. PP2A activity was investigated by the colorimetric assay. Results: The hydrophobic non-amyloid component (NAC) domain of alpha-Syn interacted with PP2A C alpha and upregulated its activity. alpha-Syn aggregates reduced its ability to upregulate PP2A activity, since the hydrophobic domain of alpha-Syn was blocked during aggregation. Furthermore, in the hydrophobic center of PP2A C alpha, the residue of I123 was responsible for PP2A to interact with alpha-Syn, and its hydrophilic mutation blocked its interaction with alpha-Syn as well as its activity upregulation by alpha-Syn. Conclusions: alpha-Syn bound to PP2A C alpha by the hydrophobic interaction and upregulated its activity. Blocking the hydrophobic domain of alpha-Syn or hydrophilic mutation on the residue I123 in PP2A C alpha all reduced PP2A activity upregulation by alpha-Syn. Overall, we explored the mechanism of alpha-Syn regulating PP2A activity, which might offer much insight into the basis underlying PD pathogenesis. (C) 2018 The Author(s) Published by S. Karger AG, Basel
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [31571202, 31271136, 81371398]; Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions [CITTCD201504087]; Clinic-Basic Fund of Capital Medical University [17034]; Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges Under Beijing Municipality [IDHT20140514]
第一作者机构：[a]Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repairing, Beijing Key Laboratory of Brain Major Disorders-State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing,
通讯作者：
通讯机构：[a]Department of Neurobiology, Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory of Neural Regeneration and Repairing, Beijing Key Laboratory of Brain Major Disorders-State Key Lab Incubation Base, Beijing Neuroscience Disciplines, Beijing,[*1]Department of Neurobiology, Capital Medical University 10 Xitoutiao, Youanmenwai, Beijing 100069 (China)
推荐引用方式(GB/T 7714)：
Jing Qu,Hongxia Yan,Yuan Zheng,et al.The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity[J].CELLULAR PHYSIOLOGY AND BIOCHEMISTRY.2018,47(6):2613-2625.doi:10.1159/000491657.
APA：
Jing Qu,Hongxia Yan,Yuan Zheng,Fenqin Xue,Yan Zheng...&Jianliang Zhang.(2018).The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity.CELLULAR PHYSIOLOGY AND BIOCHEMISTRY,47,(6)
MLA：
Jing Qu,et al."The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity".CELLULAR PHYSIOLOGY AND BIOCHEMISTRY 47..6(2018):2613-2625
