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

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

doi:10.3389/fcell.2020.564641

Abstract

IntroductionDiabetes 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 MethodsIn 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.ResultsThe 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-1S312 in blood NDEVs than controls. In addition, the p-IRS-1S312 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).ConclusionPD patients exerted altered p-IRS-1S312 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-1S312 in blood NDEVs as a segregating biomarker of PD required further cohort study to assess the association with the progression of PD.

Highlights

Diabetes increases the risk of Parkinson’s disease (PD)
Extracellular vesicles (EVs) of sizes between 30 and 75 nm were more in healthy controls than in PD patients (p = 0.0321; Figure 1G); the majority of EVs isolated from PD patient plasma were 75–150 nm in size (p = 0.0433; Figure 1H)
The present study demonstrated that in blood neuron-derived extracellular vesicles (NDEVs), the p-IRS1S312 level was significantly increased in either overall and nondiabetes PD patients compared with their counterpart controls

Summary

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. The present study investigated whether PD patients exert altered phosphorylation IRS-1 (p-IRS-1) inside the blood neuron-derived extracellular vesicles (NDEVs). 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. Several studies have suggested that diabetes increases the risk of or accelerates the progression of Parkinson’s disease (PD), (Hu et al, 2007; Cereda et al, 2011; Sun et al, 2012; Lu et al, 2014; Hong et al, 2020). No biomarker evidence exists to confirm the association between PD and neural insulin resistance

Methods

Results

Discussion

Conclusion