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

2022 ◽  
Author(s):  
Sijia Yin ◽  
Chao Han ◽  
Yun Xia ◽  
Fang Wan ◽  
Junjie Hu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Phosphatase ◽  
Essential Role ◽  
Protein Phosphatase 2A ◽  
Area Under The Curve ◽  
Alpha Synuclein ◽  
Phosphatase 2A ◽  
Induced Aggregation ◽  
Age And Sex

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.

scholarly journals Alpha-Synuclein Protofibrils in Cerebrospinal Fluid: A Potential Biomarker for Parkinson's Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 1429-1442
Author(s):  
Marianne von Euler Chelpin ◽  
Linda Söderberg ◽  
Johanna Fälting ◽  
Christer Möller ◽  
Marco Giorgetti ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Area Under The Curve ◽  
Corticobasal Degeneration ◽  
Alpha Synuclein ◽  
Cross Reactivity ◽  
Potential Biomarker ◽  
Csf Levels

Background: Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective: To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α-synuclein protofibrils (α-syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods: A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer’s disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ42)>530 pg/mL, and phosphorylated tau (p-tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α-synuclein (α-syn) levels were analyzed with a commercial ELISA-kit. Results: The assay is specific to α-syn PF, with no cross-reactivity to monomeric α-syn, or the β- and γ-synuclein variants. CSF α-syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p = 0.02). The accuracy of predicting PD using α-syn PF is significantly different from controls (area under the curve 0.68, p = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α-syn were significantly different between the PD and CBD groups (p = 0.04). Conclusion: The developed method specifically quantifies α-syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls.

scholarly journals Blood Plasma of Patients with Parkinson’s Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Peng Wang ◽  
Xin Li ◽  
Xuran Li ◽  
Weiwei Yang ◽  
Shun Yu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alternative Pathway ◽  
Lewy Bodies ◽  
Normal Subjects ◽  
Alpha Synuclein ◽  
Phosphatase 2A ◽  
Alpha Synuclein Aggregation ◽  
The Brain ◽  
Neighboring Neuron

A pathological hallmark of Parkinson’s disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn. This was supported by the observations that phosphorylated α-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote α-syn phosphorylation and aggregation. We also analyzed neurotoxicity of α-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of α-syn aggregates via an alternative pathway and accelerate progression of PD.

scholarly journals Alterations of Erythrocytic Phosphorylated Alpha-Synuclein in Different Subtypes and Stages of Parkinson's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Xu-Ying Li ◽  
Wei Li ◽  
Xin Li ◽  
Xu-Ran Li ◽  
Linjuan Sun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Duration ◽  
Late Onset ◽  
Area Under The Curve ◽  
Alpha Synuclein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
Olfactory Loss ◽  
Potential Biomarker

Serine 129-phosphorylated alpha-synuclein (pS-α-syn) is a major form of α-syn relevant to the pathogenesis of Parkinson's disease (PD), which has been recently detected in red blood cells (RBCs). However, alterations of RBC-derived pS-α-syn (pS-α-syn-RBC) in different subtypes and stages of PD remains to be investigated. In the present study, by using enzyme-linked immunosorbent assay (ELISA) to measure pS-α-syn-RBC, we demonstrated significantly higher levels of pS-α-syn-RBC in PD patients than in healthy controls. pS-α-syn-RBC separated the patients well from the controls, with a sensitivity of 93.39% (95% CI: 90.17–95.81%), a specificity of 93.11% (95% CI: 89.85–95.58%), and an area under the curve (AUC) of 0.96. Considering motor subtypes, the levels of pS-α-syn-RBC were significantly higher in late-onset than young-onset PD (p = 0.013) and in those with postural instability and gait difficulty than with tremor-dominant (TD) phenotype (p = 0.029). In addition, the levels of pS-α-syn-RBC were also different in non-motor subtypes, which were significantly lower in patients with cognitive impairment (p = 0.012) and olfactory loss (p = 0.004) than in those without such symptoms. Moreover, the levels of pS-α-syn-RBC in PD patients were positively correlated with disease duration and Hoehn &amp; Yahr stages (H&amp;Y) (p for trend =0.02 and &lt;0.001) as well as UPDRS III (R2 = 0.031, p = 0.0042) and MoCA scores (R2 = 0.048, p = 0.0004). The results obtained suggest that pS-α-syn-RBC can be used as a potential biomarker for not only separating PD patients from healthy controls but also predicting the subtypes and stages of PD.

scholarly journals Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

2019 ◽  
Vol 116 (25) ◽  
pp. 12422-12427 ◽  
Author(s):  
Mingzhu Zheng ◽  
Dan Li ◽  
Zhishan Zhao ◽  
Dmytro Shytikov ◽  
Qin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Cell Survival ◽  
Protein Phosphatase ◽  
Essential Role ◽  
Protein Phosphatase 2A ◽  
Thymocyte Development ◽  
Double Positive ◽  
Phosphatase 2A

The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2caflox/flox-Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4+ CD8+ cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival.

scholarly journals Protein phosphatase 2A has an essential role in the activation of γ-irradiation-induced G2/M checkpoint response

Oncogene ◽  
2010 ◽  
Vol 29 (30) ◽  
pp. 4317-4329 ◽  
Author(s):  
Y Yan ◽  
P T Cao ◽  
P M Greer ◽  
E S Nagengast ◽  
R H Kolb ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Essential Role ◽  
Protein Phosphatase 2A ◽  
Γ Irradiation ◽  
Checkpoint Response ◽  
Phosphatase 2A

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

Oncotarget ◽  
2017 ◽  
Vol 9 (1) ◽  
pp. 37-53 ◽  
Author(s):  
Weiwei Yang ◽  
Xue Wang ◽  
Jia Liu ◽  
Chunli Duan ◽  
Ge Gao ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Neuronal Injury ◽  
Alpha Synuclein ◽  
Phosphatase 2A

scholarly journals Scutellarin inhibits the uninduced and metal-induced aggregation of α-Synuclein and disaggregates preformed fibrils: implications for Parkinson's disease

2020 ◽  
Vol 477 (3) ◽  
pp. 645-670 ◽  
Author(s):  
Fatima Kamal Zaidi ◽  
Shashank Deep
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metal Ion ◽  
Ion Homeostasis ◽  
Transition Metal Ions ◽  
Alpha Synuclein ◽  
Higher Order ◽  
Ans Binding ◽  
Metal Ion Homeostasis ◽  
Induced Aggregation

The aggregation of the protein alpha synuclein (α-Syn), a known contributor in Parkinson's disease (PD) pathogenesis is triggered by transition metal ions through occupational exposure and disrupted metal ion homeostasis. Naturally occurring small molecules such as polyphenols have emerged as promising inhibitors of α-Syn fibrillation and toxicity and could be potential therapeutic agents against PD. Here, using an array of biophysical tools combined with cellular assays, we demonstrate that the novel polyphenolic compound scutellarin efficiently inhibits the uninduced and metal-induced fibrillation of α-Syn by acting at the nucleation stage and stabilizes a partially folded intermediate of α-Syn to form SDS-resistant, higher-order oligomers (∼680 kDa) and also disaggregates preformed fibrils of α-Syn into similar type of higher-order oligomers. ANS binding assay, fluorescence lifetime measurements and cell-toxicity experiments reveal scutellarin-generated oligomers as compact, low hydrophobicity structures with modulated surface properties and significantly reduced cytotoxicity than the fibrillation intermediates of α-Syn control. Fluorescence spectroscopy and isothermal titration calorimetry establish the binding between scutellarin and α-Syn to be non-covalent in nature and of moderate affinity (Ka ∼ 105 M−1). Molecular docking approaches suggest binding of scutellarin to the residues present in the NAC region and C-terminus of monomeric α-Syn and the C-terminal residues of fibrillar α-Syn, demonstrating inhibition of fibrillation upon binding to these residues and possible stabilization of the autoinhibitory conformation of α-Syn. These findings reveal interesting insights into the mechanism of scutellarin action and establish it as an efficient modulator of uninduced as well as metal-induced α-Syn fibrillation and toxicity.

scholarly journals Preliminary Findings on Proline-Rich Protein 14 as a Diagnostic Biomarker for Parkinson’s Disease

2020 ◽  
Author(s):  
Tao Jin ◽  
Xuling Tan ◽  
Xiaoliu Shi ◽  
Lingling Lv ◽  
Xinke Peng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Area Under The Curve ◽  
Morphological Alteration ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Potential Biomarker ◽  
Age And Sex ◽  
Proline Rich Protein

Abstract The nuclear envelope component proline-rich protein 14 (PRR14) is involved in the nuclear morphological alteration and activation of the mTOR (mammalian target of rapamycin) signaling pathway, and has been repeatedly shown to be upregulated in patients with Parkinson’s disease (PD). The aim of this study was to explore whether PRR14 can be used as a potential biomarker for the diagnosis of PD. We compared PRR14 expression in PD patients and normal controls in gene expression omnibus (GEO) data. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to detect PRR14 expression in PD patients and age- and sex-matched controls. The relationship between serum PRR14 and clinical phenotype was evaluated using correlation analysis and logistic regression. The expression of PRR14 in whole blood, substantia nigra, and medial substantia nigra was significantly higher in PD patients than in the healthy control group. Compared to plasma, serum was more suitable for the detection of PRR14. Furthermore, serum PRR14 level in PD patients was significantly higher than that in age- and sex-matched controls. The area under the curve for serum PRR14 level in the ability to identify PD versus age- and sex-matched controls was 0.786. In addition, serum PRR14 level was found to correlate with constipation in PD patients. Our findings demonstrate for the first time that serum PRR14 is a potential biomarker for PD.

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