C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci.
C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci.
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DOI：
10.1007/s00401-013-1200-z
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发表时间：
2013-12
影响因子：
12.7
通讯作者：
Isaacs AM
中科院分区：
文献类型：
--
作者：
Mizielinska S;Lashley T;Norona FE;Clayton EL;Ridler CE;Fratta P;Isaacs AM
C9orf72 基因非编码区中 GGGGCC 重复序列的扩展是额颞叶变性 (FTLD) 和肌萎缩侧索硬化症的常见原因。非编码重复扩增可能通过降低其所在基因的表达水平、产生称为RNA焦点的有毒重复RNA聚集体或通过产生由重复相关的非ATG翻译产生的有毒蛋白质而引起疾病。我们使用一系列 C9FTLD 病例以及神经退行性疾病和正常对照，提出了 C9orf72 重复正义和反义 RNA 灶的第一份明确报告。敏感和特异的荧光原位杂交方案与蛋白质免疫染色相结合，显示有义和反义焦点均频繁出现，且对 C9FTLD 具有特异性，并且存在于额叶皮层、海马和小脑的神经元中。高分辨率成像还可以准确分析病灶数量和亚细胞定位。 RNA 焦点在额叶皮质中最为丰富，其中 51% 的神经元含有焦点。 RNA 聚集点也出现在星形胶质细胞、小胶质细胞和少突胶质细胞中，但程度低于神经元。在带有 TDP-43 和 p62 包涵体的神经元中都观察到了 RNA 灶，但频率并不高于偶然预期的频率。额叶皮质中的 RNA 灶丰度与发病年龄呈显着负相关。这些数据证实，正义和反义 C9orf72 重复 RNA 灶是 C9FTLD 的一致且特定的特征，为 C9FTLD 的发病机制提供了新的见解。本文的在线版本 (doi:10.1007/s00401-013-1200-z) 包含补充材料，可供授权用户使用。
An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Non-coding repeat expansions may cause disease by reducing the expression level of the gene they reside in, by producing toxic aggregates of repeat RNA termed RNA foci, or by producing toxic proteins generated by repeat-associated non-ATG translation. We present the first definitive report of C9orf72 repeat sense and antisense RNA foci using a series of C9FTLD cases, and neurodegenerative disease and normal controls. A sensitive and specific fluorescence in situ hybridisation protocol was combined with protein immunostaining to show that both sense and antisense foci were frequent, specific to C9FTLD, and present in neurons of the frontal cortex, hippocampus and cerebellum. High-resolution imaging also allowed accurate analyses of foci number and subcellular localisation. RNA foci were most abundant in the frontal cortex, where 51 % of neurons contained foci. RNA foci also occurred in astrocytes, microglia and oligodendrocytes but to a lesser degree than in neurons. RNA foci were observed in both TDP-43- and p62-inclusion bearing neurons, but not at a greater frequency than expected by chance. RNA foci abundance in the frontal cortex showed a significant inverse correlation with age at onset of disease. These data establish that sense and antisense C9orf72 repeat RNA foci are a consistent and specific feature of C9FTLD, providing new insight into the pathogenesis of C9FTLD. The online version of this article (doi:10.1007/s00401-013-1200-z) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
64.5
作者：
Cooper TA;Wan L;Dreyfuss G
通讯作者：
Dreyfuss G
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
DOI：
10.1016/s1474-4422(12)70043-1
发表时间：
2012-04
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Majounie E;Renton AE;Mok K;Dopper EG;Waite A;Rollinson S;Chiò A;Restagno G;Nicolaou N;Simon-Sanchez J;van Swieten JC;Abramzon Y;Johnson JO;Sendtner M;Pamphlett R;Orrell RW;Mead S;Sidle KC;Houlden H;Rohrer JD;Morrison KE;Pall H;Talbot K;Ansorge O;Chromosome 9-ALS/FTD Consortium;French research network on FTLD/FTLD/ALS;ITALSGEN Consortium;Hernandez DG;Arepalli S;Sabatelli M;Mora G;Corbo M;Giannini F;Calvo A;Englund E;Borghero G;Floris GL;Remes AM;Laaksovirta H;McCluskey L;Trojanowski JQ;Van Deerlin VM;Schellenberg GD;Nalls MA;Drory VE;Lu CS;Yeh TH;Ishiura H;Takahashi Y;Tsuji S;Le Ber I;Brice A;Drepper C;Williams N;Kirby J;Shaw P;Hardy J;Tienari PJ;Heutink P;Morris HR;Pickering-Brown S;Traynor BJ
通讯作者：
Traynor BJ
影响因子：
9.9
作者：
Ratnavalli, E;Brayne, C;Hodges, JR
通讯作者：
Hodges, JR