Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene.
Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene.
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DOI：
10.1111/nan.12178
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发表时间：
2015-08
影响因子：
5
通讯作者：
Mann DM
中科院分区：
文献类型：
--
作者：
Baborie A;Griffiths TD;Jaros E;Perry R;McKeith IG;Burn DJ;Masuda-Suzukake M;Hasegawa M;Rollinson S;Pickering-Brown S;Robinson AC;Davidson YS;Mann DM
额颞叶变性（FTLD）和运动神经元疾病通过在C9 ORF 72中拥有六核苷酸重复扩增而联系在一起，并且两者都显示小脑和海马神经元内的神经元胞质内含物，其为TDP-43阴性，但对p62和二肽重复蛋白（DPR）具有免疫反应性，这些是由基因扩增区域的非ATG RAN翻译产生的。通过重复引物PCR和Southern印迹分析了来自纽卡斯尔的22例FTLD的C9 ORF 72扩增。进行了详细的病例记录分析，并通过回顾临床病史获得了盲态回顾性临床印象。对所有主要脑区的切片进行TDP-43、p62和DPR免疫染色。将扩增携带者中TDP-43和DPR病理的程度与曼彻斯特脑库中先前确定的其他13例已确诊疾病的病例进行了比较。鉴定了3名携带C9 ORF 72扩增的纽卡斯尔患者。这3例患者过早死亡，2例在发病10个月和3年内死于支气管肺炎，1例在发病3年后死于心肌梗死。在所有三个中，DPR在所有大脑皮质区域、海马和小脑中丰富，但TDP-43病理变化很少。这3例患者的DPR病理改变的严重程度与Manchester系列相似，尽管TDP-43的病理程度明显较轻。在C9 ORF 72中伴有FTLD扩展的患者中，DPR在神经细胞内的广泛蓄积可能比TDP-43早得多。
Frontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP‐43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non‐ATG RAN translation of the expanded region of the gene. Twenty‐two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP‐43, p62 and DPR. The extent of TDP‐43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease. Three Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP‐43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP‐43 pathology was significantly less. Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP‐43 in patients with FTLD bearing expansion in C9ORF72.