A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I
A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I
复制标题
DOI：
10.1016/j.mcn.2017.02.008
复制
发表时间：
2017-04-01
影响因子：
3.5
通讯作者：
Torres Aleman, I.
中科院分区：
文献类型：
--
作者：
Franco, C.;Genis, L.;Torres Aleman, I.
遗传性神经退行性疾病，如弗里德赖希共济失调（FRDA），由线粒体伴侣蛋白纤维蛋白（Fxn）缺乏引起，显示出涉及不同神经元子集的特定神经功能缺陷，尽管Fxn缺乏普遍存在。由于星形胶质细胞与神经退行性变有关，我们分析了它们是否也受到fracaxin缺乏的影响并导致疾病。我们还测试了胰岛素样生长因子I （IGF-I）是否也在体内发挥保护作用，它已被证明能有效地增加神经元和星形胶质细胞中的frataxin水平。利用发育过程中多能干细胞表达的GFAP启动子，在成年小鼠中主要由星形胶质细胞表达，我们在小鼠（FGKO小鼠）中以时间依赖的方式切除Fxn，发现在发育过程中消除Fxn会导致严重的运动失调和早期死亡，而在成年小鼠中删除Fxn则不会。机制分析显示，Fxn缺乏导致发育中的小脑星形胶质细胞生长和存活受损，而前脑星形胶质细胞生长正常。在果蝇模型中观察到星形胶质细胞中卵黄蛋白缺乏的类似时间依赖性效应。此外，用igf - 1治疗FGKO小鼠改善了它们的运动表现，减少了小脑萎缩，提高了生存率。这些观察结果表明，发育中的小脑星形细胞对Fxn缺乏的更大脆弱性可能导致这种遗传性疾病的小脑缺陷。我们的数据也证实了igf - 1对早期FRDA缺乏症的治疗益处。(C) 2017爱思唯尔公司版权所有。
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. (C) 2017 Elsevier Inc. All rights reserved.