Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations
Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations
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DOI：
10.1007/s00401-013-1181-y
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发表时间：
2013-12-01
影响因子：
12.7
通讯作者：
Neumann, Manuela
中科院分区：
文献类型：
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作者：
Mackenzie, Ian R.;Arzberger, Thomas;Neumann, Manuela
C9 ORF 72中的六核苷酸重复扩增是额颞叶痴呆和运动神经元疾病最常见的遗传原因。最近，扩展的六核苷酸重复的非常规非ATG翻译，导致二肽重复（DPR）蛋白（poly-GA、-GR和GP）的产生和聚集，被鉴定为C9 ORF 72突变的潜在病理机制。除了DPR蛋白的积累外，C9 ORF 72突变病例中的第二个神经病理学标志性病变是TDP-43的积累。在这项研究中，我们对新型单克隆抗体的特点聚-GA和进行了详细的分析DPR和TDP-43病理的神经解剖分布在一个队列的35例C9 ORF 72突变，包括广泛的临床表型。我们发现，无论小脑、所有新皮层区域（额叶、运动皮层和枕叶）和海马的DPR负荷高的表型如何，皮质下区域的中度病理和下运动神经元的最小病理，DPR病理模式在病例中高度一致。未观察到DPR病理学与神经变性程度之间的相关性，而TDP-43病理学与临床表型和关键解剖区域的变性之间存在良好关联。我们的数据证实DPR病理的存在与C9 ORF 72突变密切相关。所观察到的DPR包涵体负载和神经变性之间的解离可能表明包涵体形成作为科普可溶性毒性DPR物质的潜在保护性反应。此外，我们的数据表明，由于C9 ORF 72突变导致的TDP-43蓄积和代谢异常作为次要下游效应的改变可能在C9 ORF 72发病机制的神经退行性过程中发挥核心作用。
Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. Recently, unconventional non-ATG translation of the expanded hexanucleotide repeat, resulting in the production and aggregation of dipeptide repeat (DPR) proteins (poly-GA, -GR and GP), was identified as a potential pathomechanism of C9ORF72 mutations. Besides accumulation of DPR proteins, the second neuropathological hallmark lesion in C9ORF72 mutation cases is the accumulation of TDP-43. In this study, we characterized novel monoclonal antibodies against poly-GA and performed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in a cohort of 35 cases with the C9ORF72 mutation that included a broad spectrum of clinical phenotypes. We found the pattern of DPR pathology to be highly consistent among cases regardless of the phenotype with high DPR load in the cerebellum, all neocortical regions (frontal, motor cortex and occipital) and hippocampus, moderate pathology in subcortical areas and minimal pathology in lower motor neurons. No correlation between DPR pathology and the degree of neurodegeneration was observed, while a good association between TDP-43 pathology with clinical phenotype and degeneration in key anatomical regions was present. Our data confirm that the presence of DPR pathology is intimately related to C9ORF72 mutations. The observed dissociation between DPR inclusion body load and neurodegeneration might suggest inclusion body formation as a potentially protective response to cope with soluble toxic DPR species. Moreover, our data imply that alterations due to the C9ORF72 mutation resulting in TDP-43 accumulation and dysmetabolism as secondary downstream effects likely play a central role in the neurodegenerative process in C9ORF72 pathogenesis.