SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.
SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.
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DOI：
10.1038/ncomms16063
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发表时间：
2017-07-05
影响因子：
16.6
通讯作者：
Shaw PJ
中科院分区：
文献类型：
--
作者：
Hautbergue GM;Castelli LM;Ferraiuolo L;Sanchez-Martinez A;Cooper-Knock J;Higginbottom A;Lin YH;Bauer CS;Dodd JE;Myszczynska MA;Alam SM;Garneret P;Chandran JS;Karyka E;Stopford MJ;Smith EF;Kirby J;Meyer K;Kaspar BK;Isaacs AM;El-Khamisy SF;De Vos KJ;Ning K;Azzouz M;Whitworth AJ;Shaw PJ
C9ORF72基因中的六核苷酸重复扩增是肌萎缩侧索硬化症和额颞叶痴呆的最常见的已知遗传原因。重复转录物和二肽重复蛋白的表达触发多种神经毒性机制。重复转录本是如何从细胞核输出的尚不清楚。在这里，我们表明，核输出适配器SRSF1的耗竭防止神经退行性变和运动缺陷的果蝇模型C9ORF72相关疾病。在共培养试验中，这种干预抑制了患者源性运动神经元的细胞死亡和星形胶质细胞介导的神经毒性。我们进一步证明，无论是耗尽SRSF1或阻止其与NXF1的相互作用，特异性抑制病理性C9ORF72转录核出口，二肽重复蛋白的生产和果蝇，患者源性神经元和神经元细胞模型的神经毒性。总之，我们发现SRSF1的重复RNA螯合触发了保留扩展六核苷酸重复序列的C9ORF72转录本的NXF1依赖性核输出，并揭示了一种新的有希望的神经保护治疗靶点。ALS和额颞叶痴呆相关的C9ORF72基因的RNA通过未知的机制从细胞核输出。这项研究表明，减少核输出接头SRSF1可以减轻果蝇和患者源性诱导运动神经元中的神经元细胞死亡和C9ORF72的核输出。
Hexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection. The RNA for ALS- and frontotemporal dementia-associated C9ORF72 gene is exported from nucleus via an unknown mechanism. This study shows that reduction of nuclear export adaptor SRSF1 can alleviate neuronal cell death and nuclear export of C9ORF72 in Drosophila and patient-derived induced motor neurons.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
12.7
作者：
Cooper-Knock J;Higginbottom A;Stopford MJ;Highley JR;Ince PG;Wharton SB;Pickering-Brown S;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
DOI：
10.1093/brain/awu120
发表时间：
2014-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Cooper-Knock J;Walsh MJ;Higginbottom A;Robin Highley J;Dickman MJ;Edbauer D;Ince PG;Wharton SB;Wilson SA;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
30.8
作者：
Cartegni, L;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
16
作者：
Huang, YQ;Gattoni, R;Steitz, JA
通讯作者：
Steitz, JA