Laboratory of Research in Parkinson's Disease and Related Disorders, Health Sciences Institute, China Medical University, Shenyang, 110122, China.
Neural Plasticity and Repair Unit, Department of Experimental Medical Sciences, Lund University, 221 84, Lund, Sweden.
Transl Neurodegener. 2022 Mar 7;11(1):14. doi: 10.1186/s40035-022-00288-z.
Growing evidence suggests an association between Parkinson's disease (PD) and diabetes mellitus (DM). At the cellular level, long-term elevated levels of glucose have been shown to lead to nigrostriatal degeneration in PD models. However, the underlying mechanism is still unclear. Previously, we have elucidated the potential of type 2 diabetes mellitus (T2DM) in facilitating PD progression, involving aggregation of both alpha-synuclein (α-syn) and islet amyloid polypeptide in the pancreatic and brain tissues. However, due to the complicated effect of insulin resistance on PD onset, the actual mechanism of hyperglycemia-induced dopaminergic degeneration remains unknown.
We employed the type 1 diabetes mellitus (T1DM) model induced by streptozotocin (STZ) injection in a transgenic mouse line (BAC-α-syn-GFP) overexpressing human α-syn, to investigate the direct effect of elevated blood glucose on nigrostriatal degeneration.
STZ treatment induced more severe pathological alterations in the pancreatic islets and T1DM symptoms in α-syn-overexpressing mice than in wild-type mice, at one month and three months after STZ injections. Behavioral tests evaluating motor performance confirmed the nigrostriatal degeneration. Furthermore, there was a marked decrease in dopaminergic profiles and an increase of α-syn accumulation and Serine 129 (S129) phosphorylation in STZ-treated α-syn mice compared with the vehicle-treated mice. In addition, more severe neuroinflammation was observed in the brains of the STZ-treated α-syn mice.
Our results solidify the potential link between DM and PD, providing insights into how hyperglycemia induces nigrostriatal degeneration and contributes to pathogenic mechanisms in PD.
越来越多的证据表明帕金森病（PD）与糖尿病（DM）之间存在关联。在细胞水平上，长期高血糖已被证明会导致 PD 模型中的黑质纹状体变性。然而，其潜在机制尚不清楚。先前，我们已经阐明了 2 型糖尿病（T2DM）在促进 PD 进展中的潜力，涉及胰腺和脑组织中α-突触核蛋白（α-syn）和胰岛淀粉样多肽的聚集。然而，由于胰岛素抵抗对 PD 发病的复杂影响，高血糖诱导的多巴胺能变性的实际机制仍不清楚。
我们使用链脲佐菌素（STZ）注射诱导的 1 型糖尿病（T1DM）模型，在过表达人α-syn 的转基因小鼠系（BAC-α-syn-GFP）中，研究升高的血糖对黑质纹状体变性的直接影响。
STZ 处理在一个月和三个月后，在过表达α-syn 的小鼠中比在野生型小鼠中引起更严重的胰岛病理改变和 T1DM 症状。评估运动性能的行为测试证实了黑质纹状体变性。此外，与对照组相比，STZ 处理的α-syn 小鼠中的多巴胺能谱明显减少，α-syn 积累和丝氨酸 129（S129）磷酸化增加。此外，在 STZ 处理的α-syn 小鼠的大脑中观察到更严重的神经炎症。
我们的结果证实了 DM 和 PD 之间的潜在联系，深入了解了高血糖如何诱导黑质纹状体变性并促进 PD 的发病机制。
