Functional genomic analysis of frataxin deficiency, Illumina data. Mus musculus

Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich's ataxia Friedreich's ataxia (FRDA), the most common inherited ataxia, is characterized by focal neurodegeneration, diabetes mellitus, and life-threatening cardiomyopathy. Frataxin, which is significantly reduced in patients with this recessive disorder, is a mitochondrial iron-binding protein, but how its deficiency leads to neurodegeneration and metabolic derangements is not known. We performed microarray analysis of heart and skeletal muscle in a mouse model of frataxin deficiency, and found molecular evidence of increased lipogenesis in skeletal muscle, and alteration of fiber-type composition in heart, consistent with insulin resistance and cardiomyopathy, respectively. Since the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is known to regulate both processes, we hypothesized that dysregulation of this pathway could play a key role in frataxin deficiency. We confirmed this by showing a coordinate dysregulation of the PPARγ coactivator Pgc1a and transcription factor Srebp1 in cellular and animal models of frataxin deficiency, and in cells from FRDA patients, who have marked insulin resistance. Finally, we show that genetic modulation of the PPARγ pathway affects frataxin levels in vitro, supporting PPARγ as a novel therapeutic target in FRDA. Overall design: To compare frataxin deficient (KIKO) mice vs. WT, heart, skeletal muscle, and liver.

弗里德赖希共济失调中frataxin缺陷的功能基因组分析揭示组织特异性改变并确定PPARγ通路为治疗靶点

弗里德赖希共济失调（Friedreich's ataxia, FRDA）是最常见的遗传性共济失调类疾病，以局灶性神经退行性变、糖尿病及致死性心肌病为主要临床特征。该隐性遗传病患者体内的frataxin（Frataxin）水平显著降低，其为一种线粒体铁结合蛋白，但目前尚不明确其缺陷如何引发神经退行性变与代谢紊乱。
本研究针对frataxin缺陷小鼠模型的心脏与骨骼肌开展微阵列分析，发现骨骼肌中存在脂肪生成增加的分子证据，心脏肌纤维类型组成发生改变，分别与胰岛素抵抗及心肌病的病理表现相符。由于过氧化物酶体增殖物激活受体γ（Peroxisome Proliferator-Activated Receptor gamma, PPARγ）通路已知可调控上述两类病理过程，我们推测该通路的失调可能在frataxin缺陷中发挥关键作用。
我们通过多项实验验证了这一假说：在frataxin缺陷的细胞与动物模型，以及存在显著胰岛素抵抗的FRDA患者来源细胞中，PPARγ共激活因子Pgc1a与转录因子Srebp1均出现协同失调。最后，本研究证实，体外实验中对PPARγ通路进行遗传调控可影响frataxin的表达水平，支持PPARγ可作为FRDA的新型治疗靶点。

实验整体设计：以frataxin缺陷（KIKO）小鼠与野生型（Wild Type, WT）小鼠为对照，采集心脏、骨骼肌及肝脏组织开展分析。