Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy.
Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy.
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DOI：
10.1007/s00401-015-1429-9
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发表时间：
2015-07
影响因子：
12.7
通讯作者：
Shaw PJ
中科院分区：
文献类型：
--
作者：
Cooper-Knock J;Higginbottom A;Stopford MJ;Highley JR;Ince PG;Wharton SB;Pickering-Brown S;Kirby J;Hautbergue GM;Shaw PJ
C9ORF72的GGGGCC重复扩增代表了肌萎缩侧索硬化症(ALS)和额颞部痴呆最常见的遗传变异。我们和其他人认为，从重复序列转录的RNA是有毒的，这是通过隔离RNA结合因子来实现的。GGGGCC-Repeat(正义)和CCCCGG-Repeat(反义)分子都可以作为RNA焦点通过荧光原位杂交检测到，但它们在中枢神经系统中的相对表达模式和对疾病的贡献尚未确定。对重复扩增C9ORF72的ALS患者中枢神经系统标本的盲法检查发现，反义病灶在小脑浦肯野神经元和运动神经元中的出现频率明显高于小脑颗粒神经元，而正义焦点在小脑颗粒神经元中的出现频率显著高于小脑颗粒神经元。与此相一致的是，含有正义或反义衍生二肽重复蛋白的包涵体分别在小脑颗粒神经元和运动神经元中出现的频率明显更高。免疫组织化学和紫外光交联研究表明，正义和反义RNA分子与SRSF2、hnRNP K、hnRNP A1、ALYREF和hnRNP H/F具有相似的相互作用。这些数据表明，尽管正义和反义RNA分子可能通过其共同的蛋白结合伙伴具有相同的毒性，但在不同的中枢神经系统神经元群体中不同的表达模式可能导致它们在神经元损伤发病机制中的相对差异。此外，在肌萎缩侧索硬化症的主要病理靶点运动神经元中，反义病灶(χ2，p<0.00001)的存在而不是正义焦点(χ2，p=0.75)的存在与tdp-43的错误定位有关，这是肌萎缩侧索硬化症神经变性的标志。这对C9ORF72疾病的翻译方法有意义，此外，负责反义和正义转录的相互作用的RNA处理因子和转录激活子可能代表新的治疗靶点。本文的在线版本(doi：10.1007/s00401-0151429-9)包含补充材料，授权用户可以使用。
GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contribution to the pathogenesis of neuronal injury. Moreover in motor neurons, which are the primary target of pathology in ALS, the presence of antisense foci (χ2, p < 0.00001) but not sense foci (χ2, p = 0.75) correlated with mislocalisation of TDP-43, which is the hallmark of ALS neurodegeneration. This has implications for translational approaches to C9ORF72 disease, and furthermore interacting RNA-processing factors and transcriptional activators responsible for antisense versus sense transcription might represent novel therapeutic targets. The online version of this article (doi:10.1007/s00401-015-1429-9) contains supplementary material, which is available to authorized users.
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与C9ORF72扩张相关的额颞叶变性和运动神经元疾病中二肽重复蛋白的脑分布。
影响因子：
7.1
作者：
Davidson YS;Barker H;Robinson AC;Thompson JC;Harris J;Troakes C;Smith B;Al-Saraj S;Shaw C;Rollinson S;Masuda-Suzukake M;Hasegawa M;Pickering-Brown S;Snowden JS;Mann DM
通讯作者：
Mann DM
DOI：
10.1126/science.1254917
发表时间：
2014-09-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kwon I;Xiang S;Kato M;Wu L;Theodoropoulos P;Wang T;Kim J;Yun J;Xie Y;McKnight SL
通讯作者：
McKnight SL
影响因子：
6.1
作者：
Bengoechea, Rocio;Tapia, Olga;Berciano, Maria T.
通讯作者：
Berciano, Maria T.
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
DOI：
10.1083/jcb.200706048
发表时间：
2007-09-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Smith KP;Byron M;Johnson C;Xing Y;Lawrence JB
通讯作者：
Lawrence JB