Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice
Metabolic inflammation exacerbates dopaminergic neuronal degeneration in response to acute MPTP challenge in type 2 diabetes mice
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DOI：
10.1016/j.expneurol.2013.11.001
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发表时间：
2014-01
影响因子：
5.3
通讯作者：
Ling Wang;Ying Zhai;Li‐li Xu;Chen Qiao;Xiulan Sun;Jian-hua Ding;Ming Lu;G. Hu
中科院分区：
文献类型：
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作者：
Ling Wang;Ying Zhai;Li‐li Xu;Chen Qiao;Xiulan Sun;Jian-hua Ding;Ming Lu;G. Hu
帕金森病（Parkinson's disease，PD）是最常见的神经退行性疾病之一，以黑质多巴胺能神经元的缺失为特征。越来越多的流行病学证据表明，2型糖尿病（T2 D）可能参与PD的发病机制。然而，确切的关联和潜在的机制仍不清楚。在本研究中，ob/obanddb/db小鼠，公认的T2 D模型，急性处理与MPTP（1-甲基-4-苯基-1，2，3，6-四氢吡啶）模拟PD样神经损伤。我们发现，胰岛素信号障碍不仅发生在胰腺和肝脏，而且在中脑ofob/obanddb/db小鼠。值得注意的是，单体和寡聚体α-突触核蛋白以及内质网应激标志物（CHOP和GRP 78）的表达在T2 D小鼠的胰腺和中脑中均显著上调，伴随着NLRP 3炎性体的活化增加以产生过量的IL-1β。此外，我们发现急性MPTP给药加重了db/db小鼠黑质多巴胺能神经元的丢失，并增加了胶质细胞的活化。总的来说，这些发现表明，α-突触核蛋白积聚和神经炎症在T2 D小鼠的中脑中加重，并且T2 D小鼠对MPTP诱导的神经毒性更敏感。我们的研究表明，在PD的发展过程中，代谢性炎症加剧了DA神经元的变性，这将为PD的病因学提供新的见解。
Parkinson's disease (PD), one of the most common neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra. Increasing epidemiological evidence has indicated that type 2 diabetes (T2D) may be implicated in the pathogenesis of PD. However, the exact association and the underlying mechanism remain unclear. In the present study,ob/obanddb/dbmice, the well accepted T2D models, were acutely treated with MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to mimic PD-like neural injury. We found that insulin signaling impairment occurred not only in pancreas and livers, but also in the midbrain ofob/obanddb/dbmice. Notably, the expressions of monomeric and oligomeric α-synuclein as well as endoplasmic reticulum stress markers (CHOP and GRP78) were significantly upregulated in both pancreas and midbrain of T2D mice, accompanied by the increased activation of NLRP3 inflammasomes to produce excess IL-1β. Furthermore, we found that acute MPTP administration aggravated the loss of dopaminergic neurons and increased the activation of glial cells in the substantia nigra ofdb/dbmice. Collectively, these findings demonstrate that α-synuclein accumulation and neuroinflammation are aggravated in the midbrain of T2D mice and T2D mice are more susceptible to the neurotoxicity induced by MPTP. Our study indicates that metabolic inflammation exacerbates DA neuronal degeneration in the progress of PD, which will provide a novel insight into the etiology of PD.