Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
J Neurosci. 2010 Mar 17;30(11):4072-80. doi: 10.1523/JNEUROSCI.6348-09.2010.
Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine stretch in the protein huntingtin (Htt). HD neurons are dysfunctional at multiple levels and have increased susceptibility to stress and apoptotic stimuli. We have discovered that synthesis of the ganglioside GM1 is reduced in fibroblasts from HD patients and in cell and animal models of HD, and that decreased GM1 levels contribute to heighten HD cell susceptibility to apoptosis. The apoptotic susceptibility is recapitulated through inhibition of ganglioside synthesis in wild-type striatal cells, suggesting that decreased GM1 levels might be one of the key events leading to HD pathogenesis and progression. Administration of GM1 restores ganglioside levels in HD cells and promotes activation of AKT and phosphorylation of mutant Htt, leading to decreased mutant Htt toxicity and increased survival of HD cells. Our data identify GM1 as a potential treatment for HD.
亨廷顿病（HD）是一种由蛋白质亨廷顿（Htt）中的多聚谷氨酰胺延伸引起的神经退行性疾病。HD 神经元在多个水平上功能失调，对应激和凋亡刺激的敏感性增加。我们发现，HD 患者的成纤维细胞以及 HD 的细胞和动物模型中 GM1 神经节苷脂的合成减少，而 GM1 水平的降低导致 HD 细胞对凋亡的敏感性增加。通过抑制野生型纹状体细胞中的神经节苷脂合成可以再现凋亡易感性，这表明 GM1 水平降低可能是导致 HD 发病机制和进展的关键事件之一。GM1 的给药可恢复 HD 细胞中的神经节苷脂水平，并促进 AKT 的激活和突变型 Htt 的磷酸化，从而降低突变型 Htt 的毒性并增加 HD 细胞的存活率。我们的数据将 GM1 确定为 HD 的一种潜在治疗方法。
