Sun Yan, Guo Chuang, Yuan Lin, Li Wen, Wang Zhan-You, Yue Feng, Li Jia-Yi
Institute of Health Sciences, China Medical University, Shenyang, China.
Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Liaoning, China.
Front Neurosci. 2020 Feb 7;14:63. doi: 10.3389/fnins.2020.00063. eCollection 2020.
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.
现有证据表明，糖尿病（DM）是帕金森病（PD）的非遗传风险因素。PD和DM在发病机制上有共同之处，包括年龄、环境因素、炎症反应和蛋白质聚集等。α-突触核蛋白是PD中蛋白质内含物的主要蛋白质成分，而胰岛淀粉样多肽（IAPP）在2型糖尿病（T2DM）的β细胞中聚集形成淀粉样结构。对自发发生T2DM的猴子和年龄匹配的正常猴子进行了胰腺和脑功能、胰腺和脑α-突触核蛋白沉积以及纹状体改变的评估。与年龄匹配的正常受试者相比，我们发现自发发生T2DM的猴子胰岛中α-突触核蛋白和IAPP的积累、聚集和磷酸化增加。双重免疫荧光分析显示胰岛中α-突触核蛋白和IAPP完全重叠。此外，在T2DM猴子的大脑中，我们观察到皮质、前连合壳核和黑质中的多巴胺能神经元中α-突触核蛋白的积累和磷酸化同时增加，有趣的是，这与空腹血糖（FPG）、甘油三酯（TG）和高密度脂蛋白（HDL）水平高度相关。我们的数据表明IAPP与α-突触核蛋白之间密切相关，以及T2DM与PD之间的潜在联系，这意味着T2DM可能通过干扰胰岛和大脑中的病理性蛋白质聚集来促进PD疾病的发生和发展。
