VCP Mutations Causing Frontotemporal Lobar Degeneration Disrupt Localization of TDP-43 and Induce Cell Death
VCP Mutations Causing Frontotemporal Lobar Degeneration Disrupt Localization of TDP-43 and Induce Cell Death
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DOI：
10.1074/jbc.m900992200
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发表时间：
2009-05-01
影响因子：
4.8
通讯作者：
Cairns, Nigel J.
中科院分区：
文献类型：
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作者：
Gitcho, Michael A.;Strider, Jeffrey;Cairns, Nigel J.
额颞叶变性（FTLD）伴包涵体肌病和骨佩吉特病是一种罕见的常染色体显性遗传疾病，由VCP（含缬氨肽蛋白）基因突变引起。该疾病的神经病理学特征为额叶和颞叶萎缩、神经元丢失和神经胶质增生以及泛素阳性包涵体（FTLD-U），这些与其他散发性和家族性FTLD-U实体中所见的不同。具有VCP突变的FTLD的泛素化包涵体的主要成分是TDP-43（43 kDa的TAR DNA结合蛋白）。TDP-43蛋白病与散发性肌萎缩侧索硬化、散发性FTLD-U和大多数家族性FTLD-U相关。了解个体基因缺陷与病理性TDP-43之间的关系将有助于表征导致神经退行性变的机制。使用细胞培养模型，我们研究了突变VCP在细胞内运输、蛋白酶体功能和细胞死亡中的作用，并证明VCP基因突变1）改变TDP-43在细胞核和细胞质之间的定位，2）降低蛋白酶体活性，3）诱导内质网应激，4）增加凋亡标志物，5）损害细胞活力。这些结果表明，VCP突变诱导的神经变性是由几种机制介导的。
Frontotemporal lobar degeneration (FTLD) with inclusion body myopathy and Paget disease of bone is a rare, autosomal dominant disorder caused by mutations in the VCP (valosin-containing protein) gene. The disease is characterized neuropathologically by frontal and temporal lobar atrophy, neuron loss and gliosis, and ubiquitin-positive inclusions (FTLD-U), which are distinct from those seen in other sporadic and familial FTLD-U entities. The major component of the ubiquitinated inclusions of FTLD with VCP mutation is TDP-43 (TAR DNA-binding protein of 43 kDa). TDP-43 proteinopathy links sporadic amyotrophic lateral sclerosis, sporadic FTLD-U, and most familial forms of FTLD-U. Understanding the relationship between individual gene defects and pathologic TDP-43 will facilitate the characterization of the mechanisms leading to neurodegeneration. Using cell culture models, we have investigated the role of mutant VCP in intracellular trafficking, proteasomal function, and cell death and demonstrate that mutations in the VCP gene 1) alter localization of TDP-43 between the nucleus and cytosol, 2) decrease proteasome activity, 3) induce endoplasmic reticulum stress, 4) increase markers of apoptosis, and 5) impair cell viability. These results suggest that VCP mutation-induced neurodegeneration is mediated by several mechanisms.