Al-Mahdawi Sahar, Pinto Ricardo Mouro, Varshney Dhaval, Lawrence Lorraine, Lowrie Margaret B, Hughes Sian, Webster Zoe, Blake Julian, Cooper J Mark, King Rosalind, Pook Mark A
Biosciences, School of Health Sciences & Social Care, Brunel University, Uxbridge UB8 3PH, UK.
Genomics. 2006 Nov;88(5):580-90. doi: 10.1016/j.ygeno.2006.06.015. Epub 2006 Aug 17.
Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by an unstable GAA repeat expansion mutation within intron 1 of the FXN gene. However, the origins of the GAA repeat expansion, its unstable dynamics within different cells and tissues, and its effects on frataxin expression are not yet completely understood. Therefore, we have chosen to generate representative FRDA mouse models by using the human FXN GAA repeat expansion itself as the genetically modified mutation. We have previously reported the establishment of two lines of human FXN YAC transgenic mice that contain unstable GAA repeat expansions within the appropriate genomic context. We now describe the generation of FRDA mouse models by crossbreeding of both lines of human FXN YAC transgenic mice with heterozygous Fxn knockout mice. The resultant FRDA mice that express only human-derived frataxin show comparatively reduced levels of frataxin mRNA and protein expression, decreased aconitase activity, and oxidative stress, leading to progressive neurodegenerative and cardiac pathological phenotypes. Coordination deficits are present, as measured by accelerating rotarod analysis, together with a progressive decrease in locomotor activity and increase in weight. Large vacuoles are detected within neurons of the dorsal root ganglia (DRG), predominantly within the lumbar regions in 6-month-old mice, but spreading to the cervical regions after 1 year of age. Secondary demyelination of large axons is also detected within the lumbar roots of older mice. Lipofuscin deposition is increased in both DRG neurons and cardiomyocytes, and iron deposition is detected in cardiomyocytes after 1 year of age. These mice represent the first GAA repeat expansion-based FRDA mouse models that exhibit progressive FRDA-like pathology and thus will be of use in testing potential therapeutic strategies, particularly GAA repeat-based strategies.
弗里德赖希共济失调（FRDA）是一种神经退行性疾病，由FXN基因内含子1内不稳定的GAA重复序列扩增突变引起。然而，GAA重复序列扩增的起源、其在不同细胞和组织中的不稳定动态以及对frataxin表达的影响尚未完全明确。因此，我们选择通过使用人类FXN GAA重复序列扩增本身作为基因修饰突变来生成具有代表性的FRDA小鼠模型。我们之前报道了建立两系人类FXN YAC转基因小鼠，它们在适当的基因组背景下含有不稳定的GAA重复序列扩增。我们现在描述通过将两系人类FXN YAC转基因小鼠与杂合Fxn基因敲除小鼠杂交来生成FRDA小鼠模型。由此产生的仅表达人类来源frataxin的FRDA小鼠显示出frataxin mRNA和蛋白质表达水平相对降低、乌头酸酶活性降低以及氧化应激，导致进行性神经退行性和心脏病理表型。通过加速转棒分析测量发现存在协调缺陷，同时运动活动逐渐减少且体重增加。在背根神经节（DRG）的神经元内检测到大量空泡，在6个月大的小鼠中主要位于腰椎区域，但在1岁后扩散到颈椎区域。在老年小鼠的腰神经根内也检测到大轴突的继发性脱髓鞘。脂褐素在DRG神经元和心肌细胞中的沉积均增加，并且在1岁后在心肌细胞中检测到铁沉积。这些小鼠代表了首批基于GAA重复序列扩增的FRDA小鼠模型，它们表现出进行性的FRDA样病理，因此将用于测试潜在的治疗策略，特别是基于GAA重复序列的策略。
