Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits
Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits
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DOI：
10.1038/84818
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发表时间：
2001-02-01
期刊：
影响因子：
30.8
通讯作者：
Koenig, M
中科院分区：
文献类型：
--
作者：
Puccio, H;Simon, D;Koenig, M
Friedreich 共济失调 (FRDA) 是最常见的常染色体隐性共济失调，其特征是大感觉神经元和脊髓小脑束变性、心肌病以及糖尿病发病率增加(1,2)。 FRDA 是由 frataxin 水平严重降低引起的，frataxin 是一种功能未知的线粒体蛋白 (3)。酵母敲除模型以及 FRDA 患者心脏活检或尸检的组织学和生化数据表明，frataxin 缺陷会导致特定的铁硫蛋白缺乏和线粒体内铁积累 (4-7)。我们最近发现，小鼠体内完全缺乏 frataxin 会导致早期胚胎死亡 (8)，这表明 frataxin 在小鼠发育过程中发挥着重要作用。通过条件基因靶向方法，我们同时产生了横纹肌frataxin缺陷系和神经元/心肌frataxin缺陷系，它们共同再现了人类疾病重要的进展性病理生理学和生化特征：不涉及骨骼肌的心脏肥大、大感觉神经元功能障碍而不改变小感觉和运动神经元，以及呼吸链和乌头酸酶复合物I-III的活性缺陷，我们的模型表明，在缺乏 frataxin 的哺乳动物中，线粒体内铁的积累具有时间依赖性，这种积累发生在病理发生后和 Fe-S 依赖性酶失活后。这些突变小鼠代表了第一个评估人类疾病治疗策略的哺乳动物模型。
Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes(1,2). FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein(3) of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation(4-7). We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality(8), demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases, Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.