Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies.
Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies.
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DOI：
10.2353/ajpath.2009.080680
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发表时间：
2009-05
期刊：
影响因子：
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通讯作者：
Jianshe Wei;M. Fujita;M. Nakai;M. Waragai;A. Sekigawa;S. Sugama;T. Takenouchi;E. Masliah;M. Hashimoto
中科院分区：
文献类型：
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作者：
Jianshe Wei;M. Fujita;M. Nakai;M. Waragai;A. Sekigawa;S. Sugama;T. Takenouchi;E. Masliah;M. Hashimoto
神经节苷类可能参与帕金森病和相关疾病的发病机制，尽管控制这种参与的确切机制尚不清楚。在这项研究中，我们确定内源性神经节苷脂水平的变化是否影响突触核蛋白病细胞模型中的溶酶体病理。为此，我们使用转染α -突触核蛋白的路易体联P123H β -突触核蛋白（β -syn）神经母细胞瘤痴呆细胞作为模型系统，因为这些细胞具有广泛形成溶酶体包涵体的特征。用糖基神经酰胺合成酶抑制剂D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol （PDMP）处理这些细胞，导致溶酶体病理的各种特征，包括溶酶体活性降低、溶酶体膜通透性增强和细胞毒性增加。与这些发现一致，溶酶体膜蛋白ATP13A2和LAMP-2的表达水平显著降低，电镜显示溶酶体膜结构发生改变。此外，由于PDMP对自噬途径的抑制作用，P123H β -syn和α -突触核蛋白在PDMP处理的细胞中都有显著的积累。最后，通过在培养细胞中添加神经节苷脂，PDMP对溶酶体病理的有害影响显着改善。这些数据表明内源性神经节苷可能对突触核蛋白病的溶酶体病理起保护作用。
Gangliosides may be involved in the pathogenesis of Parkinson's disease and related disorders, although the precise mechanisms governing this involvement remain unknown. In this study, we determined whether changes in endogenous ganglioside levels affect lysosomal pathology in a cellular model of synucleinopathy. For this purpose, dementia with Lewy body-linked P123H beta-synuclein (beta-syn) neuroblastoma cells transfected with alpha-synuclein were used as a model system because these cells were characterized as having extensive formation of lysosomal inclusions bodies. Treatment of these cells with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosyl ceramide synthase, resulted in various features of lysosomal pathology, including compromised lysosomal activity, enhanced lysosomal membrane permeabilization, and increased cytotoxicity. Consistent with these findings, expression levels of lysosomal membrane proteins, ATP13A2 and LAMP-2, were significantly decreased, and electron microscopy demonstrated alterations in the lysosomal membrane structures. Furthermore, the accumulation of both P123H beta-syn and alpha-synuclein proteins was significant in PDMP-treated cells because of the suppressive effect of PDMP on the autophagy pathway. Finally, the detrimental effects of PDMP on lysosomal pathology were significantly ameliorated by the addition of gangliosides to the cultured cells. These data suggest that endogenous gangliosides may play protective roles against the lysosomal pathology of synucleinopathies.