TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases
TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases
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DOI：
10.1074/jbc.m109.012195
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发表时间：
2009-08-14
影响因子：
4.8
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Iguchi, Yohei;Katsuno, Masahisa;Sobue, Gen
已知43-kDa的TAR dna结合蛋白（TDP-43）是肌萎缩性侧索硬化症和泛素阳性包涵体额颞叶变性的泛素化包涵体特征的主要成分。虽然TDP-43是一种核蛋白，但它从受影响的神经元和神经胶质细胞的细胞核中消失，暗示TDP-43在神经变性的发病机制中功能丧失。在分化的神经2a细胞中，TDP-43的敲低抑制了神经突的生长并诱导了细胞死亡。在敲低细胞中，Rho家族成员RhoA、Rac1和Cdc42 gtpase失活，这些分子的膜定位降低。此外，TDP-43缺失显著抑制了geranylgeranyation蛋白，这是Rho家族活性和细胞内定位的关键调节因子。相反，TDP-43的过表达减轻了药理学抑制香叶基基化引起的细胞损伤。此外，香叶香叶基焦磷酸可部分恢复TDP-43敲低细胞的细胞活力和神经突生长。总之，我们的数据表明，TDP-43可能通过Rho家族gtpase的蛋白香叶酰化在维持神经元细胞形态和存活中发挥关键作用。
The 43-kDa TAR DNA-binding protein (TDP-43) is known to be a major component of the ubiquitinated inclusions characteristic of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Although TDP-43 is a nuclear protein, it disappears from the nucleus of affected neurons and glial cells, implicating TDP-43 loss of function in the pathogenesis of neurodegeneration. Here we show that the knockdown of TDP-43 in differentiated Neuro-2a cells inhibited neurite outgrowth and induced cell death. In knockdown cells, the Rho family members RhoA, Rac1, and Cdc42 GTPases were inactivated, and membrane localization of these molecules was reduced. In addition, TDP-43 depletion significantly suppressed protein geranylgeranylation, a key regulating factor of Rho family activity and intracellular localization. In contrast, overexpression of TDP-43 mitigated the cellular damage caused by pharmacological inhibition of geranylgeranylation. Furthermore administration of geranylgeranyl pyrophosphate partially restored cell viability and neurite outgrowth in TDP-43 knockdown cells. In summary, our data suggest that TDP-43 plays a key role in the maintenance of neuronal cell morphology and survival possibly through protein geranylgeranylation of Rho family GTPases.