Simon Delphine, Seznec Hervé, Gansmuller Anne, Carelle Nadège, Weber Philipp, Metzger Daniel, Rustin Pierre, Koenig Michel, Puccio Hélène
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, 67404 Illkirch cedex, France.
J Neurosci. 2004 Feb 25;24(8):1987-95. doi: 10.1523/JNEUROSCI.4549-03.2004.
Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons of the spinal cord and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Through a spatiotemporally controlled conditional gene-targeting approach, we have generated two mouse models for FRDA that specifically develop progressive mixed cerebellar and sensory ataxia, the most prominent neurological features of FRDA. Histological studies showed both spinal cord and dorsal root ganglia (DRG) anomalies with absence of motor neuropathy, a hallmark of the human disease. In addition, one line revealed a cerebellar granule cell loss, whereas both lines had Purkinje cell arborization defects. These lines represent the first FRDA models with a slowly progressive neurological degeneration. We identified an autophagic process as the causative pathological mechanism in the DRG, leading to removal of mitochondrial debris and apparition of lipofuscin deposits. These mice therefore represent excellent models for FRDA to unravel the pathological cascade and to test compounds that interfere with the degenerative process.
弗里德赖希共济失调（FRDA）是最常见的隐性共济失调，其特征为脊髓大感觉神经元变性和心肌病。它是由线粒体蛋白铁硫簇蛋白（参与铁硫簇（ISC）生物合成）水平严重降低所致。通过时空控制的条件性基因靶向方法，我们构建了两种FRDA小鼠模型，它们特异性地出现进行性混合性小脑和感觉性共济失调，这是FRDA最突出的神经学特征。组织学研究显示脊髓和背根神经节（DRG）均有异常，但无运动神经病变，这是人类疾病的一个标志。此外，一个品系显示小脑颗粒细胞丢失，而两个品系均有浦肯野细胞树突分支缺陷。这些品系代表了首个具有缓慢进行性神经变性的FRDA模型。我们确定自噬过程是DRG中的致病病理机制，导致线粒体碎片清除和脂褐素沉积出现。因此，这些小鼠是研究FRDA病理级联反应和测试干扰退行性过程化合物的优秀模型。
