Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity
Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity
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DOI：
10.1046/j.1471-4159.2003.02263.x
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发表时间：
2004-03-01
影响因子：
4.7
通讯作者：
Beal, MF
中科院分区：
文献类型：
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作者：
Klivenyi, P;Starkov, AA;Beal, MF
改变的能量代谢，包括关键线粒体酶α-酮戊二酸脱氢酶复合物（KGDHC）和丙酮酸脱氢酶复合物（PDHC）的活性降低，是许多神经退行性疾病的特征，包括阿尔茨海默病（AD）、帕金森病（PD）和亨廷顿病（HD）。二氢硫辛酰胺脱氢酶是KGDHC和PDHC的关键亚基。我们测试了缺乏二氢硫辛酰胺脱氢酶（Dld（+/-））的小鼠是否显示对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）、丙二酸和3-硝基丙酸（3-NP）的易感性增加，这些物质已被提议用于PD和HD模型。与野生型同窝对照组相比，MPTP给药导致Dld（+/-）小鼠黑质中酪氨酸羟化酶阳性神经元显著减少。在Dld（+/-）小鼠中，丙二酸和3-NP产生的纹状体损伤体积显著增加。用3-NP处理的分离的脑线粒体的研究表明，在Dld（+/-）小鼠中，琥珀酸支持的呼吸和膜电位都受到更大程度的抑制。在HD患者的壳核中也发现KGDHC活性降低。这些发现提供了进一步的证据，线粒体缺陷可能有助于神经退行性疾病的发病机制。
Altered energy metabolism, including reductions in activities of the key mitochondrial enzymes alpha-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase complex (PDHC), are characteristic of many neurodegenerative disorders including Alzheimer's Disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Dihydrolipoamide dehydrogenase is a critical subunit of KGDHC and PDHC. We tested whether mice that are deficient in dihydrolipoamide dehydrogenase (Dld(+/-)) show increased vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), malonate and 3-nitropropionic acid (3-NP), which have been proposed for use in models of PD and HD. Administration of MPTP resulted in significantly greater depletion of tyrosine hydroxylase-positive neurons in the substantia nigra of Dld(+/-) mice than that seen in wild-type littermate controls. Striatal lesion volumes produced by malonate and 3-NP were significantly increased in Dld(+/-) mice. Studies of isolated brain mitochondria treated with 3-NP showed that both succinate-supported respiration and membrane potential were suppressed to a greater extent in Dld(+/-) mice. KGDHC activity was also found to be reduced in putamen from patients with HD. These findings provide further evidence that mitochondrial defects may contribute to the pathogenesis of neurodegenerative diseases.