Cynomolgus Monkeys With Spontaneous Type-2-Diabetes-Mellitus-Like Pathology Develop Alpha-Synuclein Alterations Reminiscent of Prodromal Parkinson's Disease and Related Diseases.

Zhan-You Wang,Yan Sun,Wen Li,Lin Yuan,Jia-Yi Li,Feng Yue,Chuang Guo

doi:10.3389/fnins.2020.00063

Abstract

Available evidence suggests that diabetes mellitus (DM) is a non-genetic risk factor for Parkinson’s disease (PD). PD and DM have shared similarities in pathogenetic mechanisms, including age, environmental factors, inflammatory reaction, and protein aggregation, etc. α-Synuclein is the primary protein component in the protein inclusions in PD, while islet amyloid polypeptide (IAPP) aggregates to form amyloid structures in β cells in type 2 diabetes mellitus (T2DM). Pancreatic and cerebral functions, pancreas and brain α-synuclein deposition as well as striatal alterations, were assessed in spontaneously developed T2DM monkeys and age-matched normal monkeys. We demonstrated increased accumulation, aggregation, and phosphorylation of α-synuclein, and IAPP in the pancreatic islets of spontaneously developed T2DM monkeys, compared to the age-matched normal subjects. Double immunofluorescence analyses showed complete overlap between α-synuclein and IAPP in the pancreatic islets. In addition, in T2DM monkeys’ brain, we observed concomitantly increased accumulation and phosphorylation of α-synuclein in the cortex, pre-commissural putamen and dopaminergic neurons in the substantia nigra, which interestingly showed high correlation with levels of fasting plasma glucose (FPG), triglyceride (TG), and high density lipoprotein (HDL). Our data indicates the close association between IAPP and α-synuclein and the potential link between T2DM and PD, which implies that T2DM may facilitate PD disease onset and progress by interfering with the pathological protein aggregation both in the pancreatic islets and the brain.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease in human, after Alzheimer’s disease (AD) (Poewe et al, 2017)
Diabetes Mellitus (DM) is a systemic metabolic disease characterized by chronic progressive hyperglycemia, which is associated with abnormal insulin secretion and responses (American Diabetes Association, 2009), DM comprises Type 1 Diabetes Mellitus (T1DM) with insufficient insulin resulting from the destruction of pancreatic β cells, and Type 2 Diabetes Mellitus (T2DM) with an insulin relative deficiency, namely insulin resistance, which gives rise to a chronically elevated blood glucose level (American Diabetes Association, 2010)
We observed a significant increase of TG (p < 0.05), but a decrease of high density lipoprotein (HDL) (p < 0.001) in diabetic monkeys compared to the agematched control subjects (Figure 1)

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease in human, after Alzheimer’s disease (AD) (Poewe et al, 2017). Diabetes Mellitus (DM) is a systemic metabolic disease characterized by chronic progressive hyperglycemia, which is associated with abnormal insulin secretion and responses (American Diabetes Association, 2009), DM comprises Type 1 Diabetes Mellitus (T1DM) with insufficient insulin resulting from the destruction of pancreatic β cells, and Type 2 Diabetes Mellitus (T2DM) with an insulin relative deficiency, namely insulin resistance, which gives rise to a chronically elevated blood glucose level (American Diabetes Association, 2010) It has been well-documented that the main pathological features of T2DM are chronic insulin resistance, continuous β cell injury and β cell loss (Cerf, 2013). By 2030, the number of people affected by the disease may reach approximately 366 million worldwide (Olokoba et al, 2012)

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