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

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.

Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease

“…A high prevalence of insulin resistance was identified in a sample of 154 non-diabetic PD patients, with 58% being insulin-resistant as indicated by abnormal Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scores [ 157 ]. Dysfunctional brain insulin signaling has been shown using blood-neuron-derived extracellular vesicles, whereby PD patients display altered IRS1 phosphorylation, which is further correlated with tremor severity [ 158 ]. Despite the link, the role of insulin abnormalities in PD remains contentious, with little difference found between patients with PD and healthy controls in peripheral insulin resistance, quantified using a hyperinsulinemic-euglycemic clamp [ 71 ].…”

Probiotics treatment for Parkinson disease: a systematic review and meta-analysis of clinical trials

“…On the hand, diabetes is a well-known risk factor for PD [ 55 ], and poor glucose control is a predictor of rapid disease progression [ 56 ]. Insulin resistance triggers the significant PD pathogeneses, namely mitochondrial dysfunction and α-synuclein accumulation, and neuronal insulin resistance is remarkable in PwP [ 57 , 58 ]. Tamtaji et al demonstrated that probiotic treatment resulted in a reduction in inflammation (assessed by a high-sensitivity C-reactive protein test) and oxidative stress (assessed by glutathione levels) and an increase in insulin sensitivity [ 32 ].…”

Extracellular vesicles in the study of Alzheimer's and Parkinson's diseases: Methodologies applied from cells to biofluids

“…The levels of other plasma exosomal proteins, as the prion protein, apolipoprotein J (APOJ), ApoA1, CR1 subcomponent, cytokines, insulin receptor substrate 1 and proteasome complex proteins and several immunologic‐associated EVs surface markers, were also capable to distinguish PD cases from controls, while no differences were found for neurofilament light chain or BDNF levels (Anastasi et al, 2021; Chan et al, 2021; Chou et al, 2020; Chung, Chan, et al, 2020; Chung, Huang, et al, 2020; Kitamura et al, 2018; Leng et al, 2020; Vacchi et al, 2020; Vacchi et al, 2021). It was likewise reported that the levels of plasma NDEVs were increased in PD when compared with Controls (Ohmichi et al, 2019).…”