Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.
Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.
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DOI：
10.1371/journal.pgen.1000193
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发表时间：
2008-09-19
期刊：
影响因子：
4.5
通讯作者：
Rademakers R
中科院分区：
文献类型：
--
作者：
Rutherford NJ;Zhang YJ;Baker M;Gass JM;Finch NA;Xu YF;Stewart H;Kelley BJ;Kuntz K;Crook RJ;Sreedharan J;Vance C;Sorenson E;Lippa C;Bigio EH;Geschwind DH;Knopman DS;Mitsumoto H;Petersen RC;Cashman NR;Hutton M;Shaw CE;Boylan KB;Boeve B;Graff-Radford NR;Wszolek ZK;Caselli RJ;Dickson DW;Mackenzie IR;Petrucelli L;Rademakers R
TAR DNA结合蛋白43（TDP-43）已被确定为肌萎缩侧索硬化症（ALS）和额颞叶变性伴泛素包涵体（FTLD-U）的主要疾病蛋白，定义了一类新的神经退行性疾病：TDP-43蛋白病。最近在家族性和散发性ALS患者中报道了编码TDP-43（TARDBP）的基因中的第一个致病性突变，支持TDP-43在神经变性中的直接作用。在这项研究中，我们报告了两个新的和一个已知的突变在TARDBP的识别和功能分析，我们确定了广泛的突变分析的结果，在一个队列的296例患者与TDP-43组织病理学相关的可变神经退行性疾病。在对92例家族性ALS患者（3.3%）的分析中，在TARDBP外显子6中发现了三种不同的杂合错义突变（p.M337V，p.N345K和p.I383V），而在24例散发性ALS患者或180例其他TDP-43阳性神经退行性疾病患者中未检测到突变。在825名对照和652名散发性ALS患者中排除了p.M337V、p.N345K和p.I383V的存在。所有三种突变都影响TDP-43 C-末端部分的高度保守氨基酸残基，这些氨基酸残基已知参与蛋白质-蛋白质相互作用。ALS患者细胞系中TDP-43的生物化学分析显示，与对照细胞系相比，胱天蛋白酶切割片段（包括约25 kDa片段）显著增加。我们的研究结果支持TARDBP突变是ALS的原因。基于突变的特定C-末端位置和较小C-末端片段的积累，我们推测TARDBP突变可能通过新型蛋白质相互作用或TDP-43片段的细胞内积累导致细胞凋亡而导致毒性功能获得。疾病蛋白质在脑神经元细胞中的异常积累是许多神经退行性疾病的特征。在这些疾病中已经发现了编码积累蛋白质的基因中的罕见突变，并且对于用于研究神经变性的细胞和动物模型的开发至关重要。最近，TAR DNA结合蛋白43（TDP-43）被确定为额颞叶变性伴泛素包涵体（FTLD-U）和肌萎缩侧索硬化（ALS）患者的疾病积累蛋白。TDP-43也在20-30%的阿尔茨海默病（AD）患者的大脑中发现。在这里，我们评估了TDP-43突变是否会导致296例FTLD，ALS或AD患者的疾病。我们在92例家族性ALS患者中的3例（3.3%）中发现了3个错义突变，在AD或FTLD患者中没有发现突变。所有鉴定的突变都聚集在外显子6中，外显子6编码TDP-43蛋白C-末端部分的高度保守区域，已知该区域参与TDP-43与其他蛋白的相互作用。我们得出结论，TDP-43突变是家族性ALS的罕见原因，但到目前为止，在其他神经退行性疾病中尚未发现。
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis. The abnormal accumulation of disease proteins in neuronal cells of the brain is a characteristic feature of many neurodegenerative diseases. Rare mutations in the genes that encode the accumulating proteins have been identified in these disorders and are crucial for the development of cell and animal models used to study neurodegeneration. Recently, the TAR DNA-binding protein 43 (TDP-43) was identified as the disease accumulating protein in patients with frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). TDP-43 was also found in the brains of 20–30% of patients with Alzheimer's disease (AD). Here, we evaluated whether mutations in TDP-43 cause disease in a cohort of 296 patients presenting with FTLD, ALS or AD. We identified three missense mutations in three out of 92 familial ALS patients (3.3%), and no mutations in AD or FTLD patients. All the identified mutations clustered in exon 6, which codes for a highly conserved region in the C-terminal part of the TDP-43 protein, which is known to be involved in the interaction of TDP-43 with other proteins. We conclude that mutations in TDP-43 are a rare cause of familial ALS, but so far are not found in other neurodegenerative diseases.
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影响因子：
64.8
作者：
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通讯作者：
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