Frataxin deficiency unveils cell-context dependent actions of insulin-like growth factor I on neurons.
Frataxin deficiency unveils cell-context dependent actions of insulin-like growth factor I on neurons.
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Frataxin缺乏揭示了胰岛素样生长因子I对神经元的细胞依赖性作用。
DOI：
10.1186/1750-1326-7-51
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发表时间：
2012-10-05
影响因子：
15.1
通讯作者：
Torres-Alemán I
中科院分区：
文献类型：
--
作者：
Franco C;Fernández S;Torres-Alemán I
Friedreich‘s共济失调(FRDA)是由于线粒体铁伴侣Frataxin(FXN)缺乏引起的一种神经退行性疾病。FRDA没有治愈方法，但增加Frataxin的疾病修改策略正在研究中。由于胰岛素样生长因子I(IGF-I)对各种类型的小脑性共济失调有治疗作用，并对线粒体功能具有保护作用，因此我们探讨了该生长因子对脑细胞潜在的FXN刺激活性。IGF-I通过其典型的Akt/mTOR信号通路使Frataxin缺乏的神经元和星形胶质细胞的Frataxin水平正常化。IGF-I也能刺激正常星形胶质细胞中的Frataxin，但不能刺激正常神经元中的Frataxin，而IGF-I能在两种类型的细胞中刺激Akt/mTOR通路。IGF-I对神经元的这种细胞上下文依赖性作用表明，FXN在神经元中的内在调控不同于在星形胶质细胞中。事实上，神经元表达更高水平的Frataxin，并且比星形胶质细胞对FXN缺乏更敏感；即：只有神经元在缺少Frataxin的情况下死亡。此外，Frataxin在神经元中的半衰期比在星形胶质细胞中更短，而在蛋白酶体被阻断后，只有神经元对IGF-I有反应，Frataxin水平增加。我们还探索了IGF-I在类FRDA转基因小鼠(YG8R小鼠)中的潜在治疗作用，并发现IGF-I治疗使这些中度共济失调小鼠的运动协调正常化。与星形胶质细胞相比，暴露于IGF-I揭示了神经元中Frataxin的细胞特异性调节。总之，这些结果表明，IGF-I在Frataxin缺乏症中发挥细胞背景神经保护作用，可能在治疗上有效。
Friedreich’s ataxia (FRDA) is a neurodegenerative disease caused by deficiency of the mitochondrial iron chaperone frataxin (Fxn). FRDA has no cure, but disease-modifying strategies to increase frataxin are under study. Because insulin-like growth factor I (IGF-I) has therapeutic effects in various types of cerebellar ataxia and exerts protective actions on mitochondrial function, we explored the potential Fxn-stimulating activity of this growth factor on brain cells. IGF-I normalized frataxin levels in frataxin-deficient neurons and astrocytes through its canonical Akt/mTOR signaling pathway. IGF-I also stimulated frataxin in normal astrocytes but not in normal neurons, whereas IGF-I stimulated the Akt/mTOR pathway in both types of cells. This cell context-dependent action of IGF-I on neurons suggested that the intrinsic regulation of Fxn in neurons is different than in astrocytes. Indeed, neurons express much higher levels of frataxin and are much more sensitive to Fxn deficiency than astrocytes; i.e.: only neurons die in the absence of frataxin. In addition, the half-life of frataxin is shorter in neurons than in astrocytes, while after blockade of the proteasome only neurons responded to IGF-I with an increase in frataxin levels. We also explore a potential therapeutic utility of IGF-I in FRDA-like transgenic mice (YG8R mice) and found that treatment with IGF-I normalized motor coordination in these moderately ataxic mice. Exposure to IGF-I unveiled a cell-specific regulation of frataxin in neurons as compared to astrocytes. Collectively, these results indicate that IGF-I exerts cell-context neuroprotection in frataxin deficiency that maybe therapeutically effective.
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Frataxin缺乏症的功能基因组分析揭示了组织特异性的改变，并将PPARGAMMA途径鉴定为弗里德里希共济失调的治疗靶标。
影响因子：
3.5
作者：
Coppola G;Marmolino D;Lu D;Wang Q;Cnop M;Rai M;Acquaviva F;Cocozza S;Pandolfo M;Geschwind DH
通讯作者：
Geschwind DH
影响因子：
4.7
作者：
Bijur, GN;Jope, RS
通讯作者：
Jope, RS
影响因子：
1.7
作者：
de la Vega, AG;Buño, W;Torres-Aleman, I
通讯作者：
Torres-Aleman, I
影响因子：
--
作者：
Dunger, D;Yuen, K;Ong, K
通讯作者：
Ong, K
DOI：
10.1073/pnas.95.3.1253
发表时间：
1998-02-03
影响因子：
11.1
作者：
Fernandez, AM;de la Vega, AG;Torres-Aleman, I
通讯作者：
Torres-Aleman, I