Targeted deletion of GD3 synthase protects against MPTP-induced neurodegeneration.
Targeted deletion of GD3 synthase protects against MPTP-induced neurodegeneration.
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DOI：
10.1111/gbb.12377
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
McDonald MP
中科院分区：
文献类型：
--
作者：
Akkhawattanangkul Y;Maiti P;Xue Y;Aryal D;Wetsel WC;Hamilton D;Fowler SC;McDonald MP
帕金森病是一种使人衰弱的神经退行性疾病，无法治愈。越来越多的证据表明神经节苷脂与多种神经退行性疾病的发病机制有关，这表明了潜在的新一类治疗靶点。我们已经证明，同时增加神经保护性 GM1 神经节苷脂和减少促凋亡 GD3 神经节苷脂的干预措施（例如抑制 GD3 合酶 (GD3S) 或施用唾液酸酶）在体外和许多临床前模型中具有神经保护作用。在本研究中，我们研究了 GD3S 缺失对 1-甲基-4苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的帕金森病的影响。使用由三个系列低剂量注射（11 mg/kg/天 x 5 天，每次间隔 3 周）组成的亚慢性方案对 GD3S−/− 小鼠或对照小鼠施用 MPTP，并在每次注射后评估运动功能。用于评估帕金森症的典型测试组合未能检测到 MPTP 治疗小鼠的缺陷。更灵敏的测量——例如测力板活动计和跑步机步态参数——检测到了 MPTP 的微妙影响，其中一些在缺乏 GD3S 的小鼠中不存在。在野生型小鼠中，MPTP 破坏了黑质致密部 (SNc) 中 53% 的酪氨酸羟化酶 (TH) 阳性神经元，并减少了纹状体多巴胺 60.7%。相比之下，GD3S−/− 小鼠的病变大小仅为 22.5%，纹状体多巴胺减少了 37.2%。对不表达 TH 的 Nissl 阳性 SNc 神经元的体视学计数表明，神经保护是完整的，但某些细胞中 TH 表达受到抑制。这些结果表明，抑制 GD3S 在 MPTP 模型中具有神经保护特性，可能值得作为治疗靶点进行进一步研究。
Parkinson’s disease is a debilitating neurodegenerative condition for which there is no cure. Converging evidence implicates gangliosides in the pathogenesis of several neurodegenerative diseases, suggesting a potential new class of therapeutic targets. We have shown that interventions that simultaneously increase the neuroprotective GM1 ganglioside and decrease the pro-apoptotic GD3 ganglioside—such as inhibition of GD3 synthase (GD3S) or administration of sialidase—are neuroprotective in vitro and in a number of preclinical models. In the present study we investigated the effects of GD3S deletion on parkinsonism induced by 1-Methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP was administered to GD3S−/− mice or controls using a subchronic regimen consisting of three series of low-dose injections (11 mg/kg/day x 5 days each, 3 weeks apart), and motor function was assessed after each. The typical battery of tests used to assess parkinsonism failed to detect deficits in MPTP-treated mice. More sensitive measures—such as the force-plate actimeter and treadmill gait parameters—detected subtle effects of MPTP, some of which were absent in mice lacking GD3S. In wild-type mice MPTP destroyed 53% of the tyrosine-hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc) and reduced striatal dopamine 60.7%. In contrast, lesion size was only 22.5% in GD3S−/− mice and striatal dopamine was reduced by 37.2%. Stereological counts of Nissl-positive SNc neurons that did not express TH suggest that neuroprotection was complete but TH expression was suppressed in some cells. These results demonstrate that inhibition of GD3S has neuroprotective properties in the MPTP model may warrant further investigation as a therapeutic target.
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