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

Mol Neurobiol. 2022 Feb;59(2):1333-1344. doi: 10.1007/s12035-021-02670-w. Epub 2022 Jan 5.

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.

Keywords: Alpha-synuclein; Biomarker; CIP2A; PP2A; Parkinson’s disease.

MeSH terms

  • Animals
  • Autoantigens
  • Biomarkers / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mice
  • Neurodegenerative Diseases* / metabolism
  • Parkinson Disease* / diagnosis
  • Parkinson Disease* / drug therapy
  • Parkinson Disease* / metabolism
  • Protein Phosphatase 2 / metabolism
  • Substantia Nigra / pathology
  • alpha-Synuclein / metabolism

Substances

  • Autoantigens
  • Biomarkers
  • CIP2A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • alpha-Synuclein
  • Protein Phosphatase 2