Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A): Could It Be a Promising Biomarker and Therapeutic Target in Parkinson's Disease?

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2022 Jan 5

PMID 34984583

Authors

Sijia Yin

Chao Han

Yun Xia

Fang Wan

Junjie Hu

Liang Kou

Yadi Sun

Jiawei Wu

Yunna Li

Qiulu Zhou

Nian Xiong

Jinsha Huang

Tao Wang

Affiliations

Soon will be listed here.

Abstract

Parkinson'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.

References

Jackson-Lewis V, Przedborski S . Protocol for the MPTP mouse model of Parkinson's disease. Nat Protoc. 2007; 2(1):141-51. DOI: 10.1038/nprot.2006.342. View

Shi M, Zabetian C, Hancock A, Ginghina C, Hong Z, Yearout D . Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease. Neurosci Lett. 2010; 480(1):78-82. PMC: 2943649. DOI: 10.1016/j.neulet.2010.06.009. View

Karuppagounder S, Brahmachari S, Lee Y, Dawson V, Dawson T, Ko H . The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Sci Rep. 2014; 4:4874. PMC: 4007078. DOI: 10.1038/srep04874. View

Xie F, Gao X, Yang W, Chang Z, Yang X, Wei X . Advances in the Research of Risk Factors and Prodromal Biomarkers of Parkinson's Disease. ACS Chem Neurosci. 2018; 10(2):973-990. DOI: 10.1021/acschemneuro.8b00520. View

Soofiyani S, Hejazi M, Baradaran B . The role of CIP2A in cancer: A review and update. Biomed Pharmacother. 2017; 96:626-633. DOI: 10.1016/j.biopha.2017.08.146. View

Liu G, Chen M, Mi N, Yang W, Li X, Wang P . Increased oligomerization and phosphorylation of α-synuclein are associated with decreased activity of glucocerebrosidase and protein phosphatase 2A in aging monkey brains. Neurobiol Aging. 2015; 36(9):2649-59. DOI: 10.1016/j.neurobiolaging.2015.06.004. View

Majbour N, Vaikath N, van Dijk K, Ardah M, Varghese S, Vesterager L . Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease. Mol Neurodegener. 2016; 11:7. PMC: 4717559. DOI: 10.1186/s13024-016-0072-9. View

Junttila M, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T . CIP2A inhibits PP2A in human malignancies. Cell. 2007; 130(1):51-62. DOI: 10.1016/j.cell.2007.04.044. View

Wang Y, Liu J, Chen M, Du T, Duan C, Gao G . The novel mechanism of rotenone-induced α-synuclein phosphorylation via reduced protein phosphatase 2A activity. Int J Biochem Cell Biol. 2016; 75:34-44. DOI: 10.1016/j.biocel.2016.03.007. View

10.

Karl T, Pabst R, von Horsten S . Behavioral phenotyping of mice in pharmacological and toxicological research. Exp Toxicol Pathol. 2003; 55(1):69-83. DOI: 10.1078/0940-2993-00301. View

11.

Lee K, Chen W, Junn E, Im J, Grosso H, Sonsalla P . Enhanced phosphatase activity attenuates α-synucleinopathy in a mouse model. J Neurosci. 2011; 31(19):6963-71. PMC: 5038983. DOI: 10.1523/JNEUROSCI.6513-10.2011. View

12.

Parnetti L, Gaetani L, Eusebi P, Paciotti S, Hansson O, El-Agnaf O . CSF and blood biomarkers for Parkinson's disease. Lancet Neurol. 2019; 18(6):573-586. DOI: 10.1016/S1474-4422(19)30024-9. View

13.

Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg M . alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002; 4(2):160-4. DOI: 10.1038/ncb748. View

14.

Wang L, Liu Y, Yan S, Du T, Fu X, Gong X . Disease Progression-Dependent Expression of CD200R1 and CX3CR1 in Mouse Models of Parkinson's Disease. Aging Dis. 2020; 11(2):254-268. PMC: 7069458. DOI: 10.14336/AD.2019.0615. View

15.

Xu J, Fu X, Pan M, Zhou X, Chen Z, Wang D . Mitochondrial Creatine Kinase is Decreased in the Serum of Idiopathic Parkinson's Disease Patients. Aging Dis. 2019; 10(3):601-610. PMC: 6538214. DOI: 10.14336/AD.2018.0615. View

16.

Kerosuo L, Fox H, Perala N, Ahlqvist K, Suomalainen A, Westermarck J . CIP2A increases self-renewal and is linked to Myc in neural progenitor cells. Differentiation. 2010; 80(1):68-77. DOI: 10.1016/j.diff.2010.04.003. View

17.

Mollenhauer B, Locascio J, Schulz-Schaeffer W, Sixel-Doring F, Trenkwalder C, Schlossmacher M . α-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol. 2011; 10(3):230-40. DOI: 10.1016/S1474-4422(11)70014-X. View

18.

Soo Hoo L, Zhang J, Chan E . Cloning and characterization of a novel 90 kDa 'companion' auto-antigen of p62 overexpressed in cancer. Oncogene. 2002; 21(32):5006-15. DOI: 10.1038/sj.onc.1205625. View

19.

Liu X, Cao W, Qin S, Zhang T, Zheng J, Dong Y . Overexpression of CIP2A is associated with poor prognosis in multiple myeloma. Signal Transduct Target Ther. 2017; 2:17013. PMC: 5661621. DOI: 10.1038/sigtrans.2017.13. View

20.

Chen L, Feany M . Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci. 2005; 8(5):657-63. DOI: 10.1038/nn1443. View