PINK1 suppresses alpha-synuclein-induced neuronal injury: a novel mechanism in protein phosphatase 2A activation

AbstractParkinson’s disease (PD) is an incurable neurodegenerative disease characterized by aggregation of pathological alpha-synuclein (α-syn) and loss of dopaminergic neuron in the substantia nigra. Inhibition of phosphorylation of the α-syn has been shown to mediate alleviation of PD-related pathology. Protein phosphatase 2A (PP2A), an important serine/threonine phosphatase, plays an essential role in catalyzing dephosphorylation of the α-syn. Here, we identified and validated cancerous inhibitor of PP2A (CIP2A), as a potential diagnostic biomarker for PD. Our data showed that plasma CIP2A concentrations in PD patients were significantly lower compared to age- and sex-matched controls, 1.721 (1.435–2.428) ng/ml vs 3.051(2.36–5.475) ng/ml, p < 0.0001. The area under the curve of the plasma CIP2A in distinguishing PD from the age- and sex-matched controls was 0.776. In addition, we evaluated the role of CIP2A in PD-related pathogenesis in PD cellular and MPTP-induced mouse model. The results demonstrated that CIP2A is upregulated in PD cellular and MPTP-induced mouse models. Besides, suppression of the CIP2A expression alleviates rotenone induced aggregation of the α-syn as well as phosphorylation of the α-syn in SH-SY5Y cells, which is associated with increased PP2A activity. Taken together, our data demonstrated that CIP2A plays an essential role in the mechanisms related to PD development and might be a novel PD biomarker.

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Senkyunolide A protects neural cells against corticosterone-induced apoptosis by modulating protein phosphatase 2A and α-synuclein signaling

Drug Design Development and Therapy ◽

10.2147/dddt.s161748 ◽

2018 ◽

Vol Volume 12 ◽

pp. 1865-1879 ◽

Cited By ~ 5

Author(s):

Shenglan Gong ◽

Jin Zhang ◽

Zhouke Guo ◽

Wenjun Fu

Keyword(s):

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Alpha Synuclein ◽

Neural Cells ◽

Phosphatase 2A ◽

Induced Apoptosis

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

Cellular Physiology and Biochemistry ◽

10.1159/000491657 ◽

2018 ◽

Vol 47 (6) ◽

pp. 2613-2625 ◽

Cited By ~ 3

Author(s):

Jing Qu ◽

Hongxia Yan ◽

Yuan Zheng ◽

Fenqin Xue ◽

Yan Zheng ◽

...

Keyword(s):

Affinity Chromatography ◽

Molecular Mechanism ◽

Protein Phosphatase ◽

Colorimetric Assay ◽

Protein Phosphatase 2A ◽

Recombinant Baculovirus ◽

Alpha Synuclein ◽

Hydrophobic Domain ◽

Pp2a Activity ◽

Phosphatase 2A

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.

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