Franco C, Genis L, Navarro J A, Perez-Domper P, Fernandez A M, Schneuwly S, Torres Alemán I
Cajal Institute, CSIC, Madrid, Spain; CIBERNED, Spain.
Regensburg University, Regensburg, Germany.
Mol Cell Neurosci. 2017 Apr;80:100-110. doi: 10.1016/j.mcn.2017.02.008. Epub 2017 Mar 7.
Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions. Using the GFAP promoter expressed by multipotential stem cells during development and mostly by astrocytes in the adult, we ablated Fxn in a time-dependent manner in mice (FGKO mice) and found severe ataxia and early death when Fxn was eliminated during development, but not when deleted in the adult. Analysis of underlying mechanisms revealed that Fxn deficiency elicited growth and survival impairments in developing cerebellar astrocytes, whereas forebrain astrocytes grew normally. A similar time-dependent effect of frataxin deficiency in astrocytes was observed in a fly model. In addition, treatment of FGKO mice with IGF-I improved their motor performance, reduced cerebellar atrophy, and increased survival. These observations indicate that a greater vulnerability of developing cerebellar astrocytes to Fxn deficiency may contribute to cerebellar deficits in this inherited disease. Our data also confirm a therapeutic benefit of IGF-I in early FRDA deficiency.
遗传性神经退行性疾病，如弗里德赖希共济失调（FRDA），由线粒体伴侣蛋白frataxin（Fxn）缺乏引起，尽管Fxn缺乏是普遍存在的，但该疾病表现出涉及不同神经元亚群的特定神经功能缺陷。由于星形胶质细胞参与神经退行性变，我们分析了它们是否也受frataxin缺乏的影响并对该疾病有影响。我们还测试了已被证明在增加神经元和星形胶质细胞中frataxin水平方面有效的胰岛素样生长因子I（IGF-I）是否也具有体内保护作用。利用多能干细胞在发育过程中表达且在成体中主要由星形胶质细胞表达的GFAP启动子，我们在小鼠中以时间依赖性方式敲除Fxn（FGKO小鼠），发现在发育过程中消除Fxn时出现严重共济失调和早期死亡，但在成体中敲除时则不会。对潜在机制的分析表明，Fxn缺乏在发育中的小脑星形胶质细胞中引发生长和存活障碍，而前脑星形胶质细胞正常生长。在果蝇模型中也观察到了星形胶质细胞中frataxin缺乏的类似时间依赖性效应。此外，用IGF-I治疗FGKO小鼠可改善其运动性能、减少小脑萎缩并延长生存期。这些观察结果表明，发育中的小脑星形胶质细胞对Fxn缺乏的更大易感性可能导致这种遗传性疾病中的小脑缺陷。我们的数据还证实了IGF-I在早期FRDA缺乏中的治疗益处。
