A new subtype of frontotemporal lobar degeneration with FUS pathology
A new subtype of frontotemporal lobar degeneration with FUS pathology
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DOI：
10.1093/brain/awp214
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发表时间：
2009-11-01
期刊：
影响因子：
14.5
通讯作者：
Mackenzie, Ian R. A.
中科院分区：
文献类型：
--
作者：
Neumann, Manuela;Rademakers, Rosa;Mackenzie, Ian R. A.
额颞叶痴呆（FTD）是一种具有异质性分子基础的临床综合征。与大多数FTD相关的神经病理学特征为Mr 43 kDa的反式反应DNA结合蛋白（TDP-43）或tau蛋白的异常细胞聚集。然而，我们最近描述了一个FTD患者亚组（约占10%），其临床表型和病理学异常，特征为额颞叶变性伴由不明泛素化蛋白组成的神经元包涵体（非典型FTLD-U; aFTLD-U）。所有病例均为散发性，均为早发性FTD，伴重度进行性行为和人格改变，无失语或显著运动特征。肉瘤融合基因（FUS）的突变最近被确定为家族性肌萎缩侧索硬化症的病因，这些病例报告有FUS蛋白异常细胞积聚。由于FTD和肌萎缩侧索硬化之间公认的临床、遗传和病理重叠，我们研究了FUS是否也可能是aFTLD-U的病理蛋白。在我们所有的aFTLD-U病例（n = 15）中，FUS免疫组化标记了所有神经元包涵体，并显示了以前未识别的神经胶质病理学。从死后aFTLD-U脑组织中提取的蛋白质的免疫印迹分析表明不溶性FUS水平增加。在我们的任何患者中均未发现FUS基因突变。这些结果表明，FUS是散发性FTD的重要亚组中的病理蛋白，并加强了FTD和肌萎缩侧索硬化症密切相关的概念。
Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10%, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related conditions.