Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.
Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72.
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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。
DOI：
10.1186/2051-5960-2-70
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发表时间：
2014-06-20
影响因子：
7.1
通讯作者：
Mann DM
中科院分区：
文献类型：
--
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
C9ORF72基因的六核苷酸（GGGGCC）扩增是家族性额颞叶变性（FTLD）和家族性运动神经元病（MND）中最常见的遗传变化。病理上，扩增载体在小脑和海马神经元内显示特征性的p62阳性，TDP-43阴性包涵体，这些包涵体也含有由扩增重复区域本身的正义和反义RAN（重复相关的非atg启动）翻译形成的二肽重复蛋白（DPR）。因此，DPR的“不适当”形成和聚集可能导致神经毒性并影响临床表型。因此，我们使用poly-GA的多克隆抗体比较了8例额颞叶痴呆（FTD）患者、6例FTD + MND患者和7例单独MND患者（所有21例患者C9ORF72扩增）的DPR脑地形分布，并将其与大脑皮层和海马关键区域的TDP-43病理程度联系起来。在FTD组、FTD + MND组和MND组之间，DPR的脑分布模式和严重程度均无显著差异，扩张载体中DPR的分布与TDP-43病理之间也没有任何关系。同样，在C9ORF72扩增的FTLD患者和未扩增的FTLD患者之间，TDP-43的病理程度也没有显著差异。DPR病理程度与TMEM106B或APOE基因型之间无相关性。然而，DPR病理程度与发病年龄呈负相关。因此，目前的研究结果表明，尽管DPR的存在和地形分布可能与C9ORF72中患有扩张的患者的诊断相关，但与临床表型的确定无关。由于TDP-43在扩增者和非扩增者中的病理相似，扩增可能是FTLD和MND的主要遗传危险因素，使大脑极易受到散发疾病中产生FTLD和MND的相同因素的影响。本文的在线版本（doi:10.1186/2051-5960-2-70）包含补充材料，可供授权用户使用。
A hexanucleotide (GGGGCC) expansion in C9ORF72 gene is the most common genetic change seen in familial Frontotemporal Lobar Degeneration (FTLD) and familial Motor Neurone Disease (MND). Pathologically, expansion bearers show characteristic p62 positive, TDP-43 negative inclusion bodies within cerebellar and hippocampal neurons which also contain dipeptide repeat proteins (DPR) formed from sense and antisense RAN (repeat associated non ATG-initiated) translation of the expanded repeat region itself. ‘Inappropriate’ formation, and aggregation, of DPR might therefore confer neurotoxicity and influence clinical phenotype. Consequently, we compared the topographic brain distribution of DPR in 8 patients with Frontotemporal dementia (FTD), 6 with FTD + MND and 7 with MND alone (all 21 patients bearing expansions in C9ORF72) using a polyclonal antibody to poly-GA, and related this to the extent of TDP-43 pathology in key regions of cerebral cortex and hippocampus. There were no significant differences in either the pattern or severity of brain distribution of DPR between FTD, FTD + MND and MND groups, nor was there any relationship between the distribution of DPR and TDP-43 pathologies in expansion bearers. Likewise, there were no significant differences in the extent of TDP-43 pathology between FTLD patients bearing an expansion in C9ORF72 and non-bearers of the expansion. There were no association between the extent of DPR pathology and TMEM106B or APOE genotypes. However, there was a negative correlation between the extent of DPR pathology and age at onset. Present findings therefore suggest that although the presence and topographic distribution of DPR may be of diagnostic relevance in patients bearing expansion in C9ORF72 this has no bearing on the determination of clinical phenotype. Because TDP-43 pathologies are similar in bearers and non-bearers of the expansion, the expansion may act as a major genetic risk factor for FTLD and MND by rendering the brain highly vulnerable to those very same factors which generate FTLD and MND in sporadic disease. The online version of this article (doi:10.1186/2051-5960-2-70) 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：
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：
3.5
作者：
Brady, Owen A.;Zheng, Yanqiu;Hu, Fenghua
通讯作者：
Hu, Fenghua
影响因子：
4.2
作者：
Bernardi, L;Maletta, RG;Bruni, AC
通讯作者：
Bruni, AC
影响因子：
12.7
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
通讯作者：
Shaw, Christopher E.