Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrnl) mutant mice
Mitochondrial dysfunction precedes neurodegeneration in mahogunin (Mgrnl) mutant mice
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DOI：
10.1016/j.neurobiolaging.2007.07.012
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发表时间：
2007-12-01
影响因子：
4.2
通讯作者：
Gunn, Teresa M.
中科院分区：
文献类型：
--
作者：
Sun, Kaihua;Johnson, Brian S.;Gunn, Teresa M.
氧化应激、泛素化缺陷和线粒体功能障碍通常与神经变性相关。缺乏mahogunin无名指-1（MGRN 1）或吸引素（ATRN）的小鼠通过未知机制发生年龄依赖性海绵状神经变性。有人认为，它们在一个共同的途径中发挥作用。由于MGRN 1是一种E3泛素连接酶，因此对Mgrn 1突变体和对照脑进行蛋白质组学分析，以探索MGRN 1缺失通过其底物积累导致神经变性的假设。Mgrn 1突变体中许多线粒体蛋白质减少。随后的分析证实，突变体大脑中线粒体复合物IV的表达和活性显著降低，氧化应激增加。线粒体功能障碍是明显的空泡化发生前数月，暗示这是一个致病因素。与ATRN和MGRN 1在相同途径中起作用的假设一致，在Atrn突变体的脑中也观察到线粒体功能障碍和增加的氧化应激。我们的研究结果表明，对Mgrn 1和Atrn突变小鼠的研究将为许多神经退行性疾病的致病分子机制提供深入了解。(C)2007年爱思唯尔公司All rights reserved.
Oxidative stress, ubiquitination defects and mitochondrial dysfunction are commonly associated with neurodegeneration. Mice lacking mahogunin ring finger-1 (MGRN1) or attractin (ATRN) develop age-dependent spongiform neurodegeneration through an unknown mechanism. It has been suggested that they act in a common pathway. As MGRN1 is an E3 ubiquitin ligase, proteomic analysis of Mgrn1 mutant and control brains was performed to explore the hypothesis that loss of MGRN1 causes neurodegeneration via accumulation of its substrates. Many mitochondrial proteins were reduced in Mgrn1 mutants. Subsequent assays confirmed significantly reduced mitochondrial complex IV expression and activity as well as increased oxidative stress in mutant brains. Mitochondrial dysfunction was obvious many months before onset of vacuolation, implicating this as a causative factor. Compatible with the hypothesis that ATRN and MGRN 1 act in the same pathway, mitochondria) dysfunction and increased oxidative stress were also observed in the brains of Atrn mutants. Our results suggest that the study of Mgrn1 and Atrn mutant mice will provide insight into a causative molecular mechanism common to many neurodegenerative disorders. (C) 2007 Elsevier Inc. All rights reserved.