Enhanced autophagy and mitochondrial aberrations in murine GM1-gangliosidosis
Enhanced autophagy and mitochondrial aberrations in murine GM1-gangliosidosis
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DOI：
10.1016/j.bbrc.2007.12.187
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发表时间：
2008-03-14
影响因子：
3.1
通讯作者：
Nanba, Eiji
中科院分区：
文献类型：
--
作者：
Takamura, Ayumi;Higaki, Katsumi;Nanba, Eiji
G（M1）-神经节苷脂沉积症是一种常染色体隐性溶酶体脂质沉积症，由溶酶体β-半乳糖苷酶（β-gal）突变引起，并导致G（M1）蓄积。神经退行性变的潜在机制知之甚少。在这里，我们证明了在β-半乳糖缺乏（β-半乳糖（-/-））小鼠脑中增加的自噬，如LC 3-II和beclin-1水平升高所证明的。发现β-gal（-/-）脑中自噬的激活伴随着增强的Akt-mTOR和Erk信号传导。此外，beta-gal（-/-）小鼠脑和培养的星形胶质细胞线粒体细胞色素c氧化酶活性显著降低。从β-gal（-/-）星形胶质细胞分离的线粒体形态异常，膜电位降低。这些细胞比野生型细胞对氧化应激更敏感，并且这种敏感性被ATP、自噬抑制剂3-甲基腺嘌呤和泛半胱天冬酶抑制剂z-VAD-fink抑制。这些结果表明，自噬激活导致G（M1）-神经节苷脂沉积症的脑中线粒体功能障碍。(C)2008年爱思唯尔公司All rights reserved.
G(M1)-gangliosidosis is an autosomal recessive lysosornal lipid storage disorder, caused by mutations of the lysosomal beta-galactosidase (beta-gal) and results in the accumulation of G(M1). The underlying mechanisms of neurodegeneration are poorly understood. Here we demonstrate increased autophagy in beta-gal-deficient (beta-gal(-/-)) mouse brains as evidenced by elevation of LC3-II and beclin-1 levels. Activation of autophagy in the beta-gal(-/-) brain was found to be accompanied with enhanced Akt-mTOR and Erk signaling. In addition, the mitochondrial cytochrome c oxidase activity was significantly decreased in brains and cultured astrocytes from beta-gal(-/-) mouse. Mitochondria isolated from beta-gal(-/-) astrocytes were morphologically abnormal and had a decreased membrane potential. These cells were more sensitive to oxidative stress than wild type cells and this sensitivity was suppressed by ATP, an autophagy inhibitor 3-methyladenine and a pan-caspase inhibitor z-VAD-fink. These results suggest activation of autophagy leading to mitochondrial dysfunction in the brain of G(M1)-gangliosidosis. (C) 2008 Elsevier Inc. All rights reserved.