C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten.
C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten.
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DOI：
10.1093/hmg/ddx022
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发表时间：
2017-03-15
影响因子：
3.5
通讯作者：
Shaw PJ
中科院分区：
文献类型：
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作者：
Stopford MJ;Higginbottom A;Hautbergue GM;Cooper-Knock J;Mulcahy PJ;De Vos KJ;Renton AE;Pliner H;Calvo A;Chio A;Traynor BJ;Azzouz M;Heath PR;ITALSGEN Consortium, NeuroX Consortium;Kirby J;Shaw PJ
肌萎缩性侧索硬化症（ALS）是一种毁灭性的、无法治愈的神经退行性疾病，其特征是神经肌肉系统的进行性衰竭。C9ORF72中A (G4C2)n重复扩增是ALS和额颞叶痴呆（FTD）最常见的遗传原因。迄今为止，证据的平衡表明（G4C2）n重复通过获得毒性功能机制引起毒性和神经变性；要么通过直接的RNA毒性，要么通过产生有毒的聚集二肽重复蛋白。在这里，我们建立了一个稳定的等基因运动神经元NSC34细胞模型，诱导表达（G4C2）102重复序列，以研究获得毒性功能机制。（G4C2）102重复序列的表达产生RNA焦点，并进行RAN翻译。此外，（G4C2）102重复序列的表达表现出细胞毒性。通过比较来自C9ORF72-ALS患者的细胞模型和激光捕获的脊髓运动神经元的转录组学数据，我们也证明了PI3K/Akt细胞存活信号通路在这两个系统中都是失调的。此外，在C9ORF72-ALS的NSC34 (G4C2)102细胞毒性获得功能模型中观察到，Pten的部分敲低可以挽救毒性。我们的数据表明，PTEN可能提供一个潜在的治疗靶点，以改善（G4C2）n重复的毒性作用。
Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease, characterised by progressive failure of the neuromuscular system. A (G4C2)n repeat expansion in C9ORF72 is the most common genetic cause of ALS and frontotemporal dementia (FTD). To date, the balance of evidence indicates that the (G4C2)n repeat causes toxicity and neurodegeneration via a gain-of-toxic function mechanism; either through direct RNA toxicity or through the production of toxic aggregating dipeptide repeat proteins. Here, we have generated a stable and isogenic motor neuronal NSC34 cell model with inducible expression of a (G4C2)102 repeat, to investigate the gain-of-toxic function mechanisms. The expression of the (G4C2)102 repeat produces RNA foci and also undergoes RAN translation. In addition, the expression of the (G4C2)102 repeat shows cellular toxicity. Through comparison of transcriptomic data from the cellular model with laser-captured spinal motor neurons from C9ORF72-ALS cases, we also demonstrate that the PI3K/Akt cell survival signalling pathway is dysregulated in both systems. Furthermore, partial knockdown of Pten rescues the toxicity observed in the NSC34 (G4C2)102 cellular gain-of-toxic function model of C9ORF72-ALS. Our data indicate that PTEN may provide a potential therapeutic target to ameliorate toxic effects of the (G4C2)n repeat.