Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson's Disease

Szu-Yi Chou; Lung Chan; Chen-Chih Chung; Jing-Yuan Chiu; Yi-Chen Hsieh; Chien-Tai Hong

doi:10.3389/fcell.2020.564641

Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson's Disease

Front Cell Dev Biol. 2020 Dec 3:8:564641. doi: 10.3389/fcell.2020.564641. eCollection 2020.

Authors

Szu-Yi Chou^{1

2}, Lung Chan^{3

4}, Chen-Chih Chung^{3

4

5}, Jing-Yuan Chiu¹, Yi-Chen Hsieh^{1

6}, Chien-Tai Hong^{3

4}

Affiliations

¹ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
² Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, Taiwan.
³ Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
⁴ Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan.
⁶ Master Program in Applied Molecular Epidemiology, College of Public Health, Taipei Medical University, Taipei, Taiwan.

Abstract

Introduction: Diabetes increases the risk of Parkinson's disease (PD). The phosphorylation of type 1 insulin receptor substrate (IRS-1) determines the function of insulin signaling pathway. Extracellular vesicles (EVs) are emerging as biomarkers of human diseases. The present study investigated whether PD patients exert altered phosphorylation IRS-1 (p-IRS-1) inside the blood neuron-derived extracellular vesicles (NDEVs).

Research design and methods: In total, there were 94 patients with PD and 63 healthy controls recruited and their clinical manifestations were evaluated. Blood NDEVs were isolated using the immunoprecipitation method, and Western blot analysis was conducted to assess total IRS-1, p-IRS-1, and downstream substrates level in blood NDEVs. Statistical analysis was performed using SPSS 19.0, and p < 0.05 was considered significant.

Results: The isolated blood EVs were validated according to the presence of CD63 and HSP70, nanoparticle tracking analysis and transmission electron microscopy. NDEVs were positive with neuronal markers. PD patients exerted significantly higher level of p-IRS-1^S312 in blood NDEVs than controls. In addition, the p-IRS-1^S312 levels in blood NDEVs was positively associated with the severity of tremor in PD patients after adjusting of age, sex, hemoglobin A1c, and body mass index (BMI).

Conclusion: PD patients exerted altered p-IRS-1^S312 in the blood NDEVs, and also correlated with the severity of tremor. These findings suggested the association between dysfunctional insulin signaling pathway with PD. The role of altered p-IRS-1^S312 in blood NDEVs as a segregating biomarker of PD required further cohort study to assess the association with the progression of PD.

Keywords: Parkinson’s disease; biomarker; diabetes; extracellular vesicle; insulin receptor substrate-1.