The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity

• Main Authors: Jing Qu, Hongxia Yan, Yuan Zheng, Fenqin Xue, Yan Zheng, Hongjuan Fang, Yongchang Chang, Hui Yang, Jianliang Zhang
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2018-07-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Alpha-synuclein; Protein phosphatase 2A; Parkinson’s disease
• Online Access: https://www.karger.com/Article/FullText/491657
• ISSN: 1015-8987; 1421-9778

Background/Aims: Alpha-synuclein (α-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. α-Syn can directly upregulate PP2A activity, but the underling mechanism remains unclear. Therefore, we investigated the molecular mechanism of α-Syn regulating PP2A activity. Methods: α-Syn and its truncations were expressed in E.coli, and purified by affinity chromatography. PP2A Cα and its mutants were expressed in recombinant baculovirus, and purified by affinity chromatography combined with gel filtration chromatography. The interaction between α-Syn and PP2A Cα was detected by GST pull-down assay. PP2A activity was investigated by the colorimetric assay. Results: The hydrophobic non-amyloid component (NAC) domain of α-Syn interacted with PP2A Cα and upregulated its activity. α-Syn aggregates reduced its ability to upregulate PP2A activity, since the hydrophobic domain of α-Syn was blocked during aggregation. Furthermore, in the hydrophobic center of PP2A Cα, the residue of I123 was responsible for PP2A to interact with α-Syn, and its hydrophilic mutation blocked its interaction with α-Syn as well as its activity upregulation by α-Syn. Conclusions: α-Syn bound to PP2A Cα by the hydrophobic interaction and upregulated its activity. Blocking the hydrophobic domain of α-Syn or hydrophilic mutation on the residue I123 in PP2A Cα all reduced PP2A activity upregulation by α-Syn. Overall, we explored the mechanism of α-Syn regulating PP2A activity, which might offer much insight into the basis underlying PD pathogenesis.