Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes.
Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes.
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DOI：
10.1093/hmg/ddt005
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发表时间：
2013-04-15
影响因子：
3.5
通讯作者：
Hirth F
中科院分区：
文献类型：
--
作者：
Diaper DC;Adachi Y;Sutcliffe B;Humphrey DM;Elliott CJ;Stepto A;Ludlow ZN;Vanden Broeck L;Callaerts P;Dermaut B;Al-Chalabi A;Shaw CE;Robinson IM;Hirth F
TDP-43 的细胞质积聚和核清除是肌萎缩侧索硬化症和额颞叶变性的家族性和散发性特征，表明 TDP-43 功能的丧失或获得，或两者兼而有之，都会导致疾病的形成。在这里，我们系统地比较了果蝇 TDP-43、TAR DNA 结合蛋白同源物 (TBPH) 在突触功能和形态、运动控制和年龄相关神经元存活方面的功能丧失和获得。 TBPH 的损失和增加都会严重影响发育并导致过早死亡。 TBPH 功能障碍导致幼虫神经肌肉接头 (NMJ) 和成虫的突触传递受损。组织特异性敲除以及幼虫 NMJ 的电生理记录也表明 TBPH 功能的改变主要影响突触前功效，表明突触前传递受损是 TDP-43 相关发病机制中最早的事件之一。成人 TBPH 的长期丢失和增加会导致突触缺陷和与年龄相关的运动控制神经元进行性退化。 TBPH 的毒性增益不会下调或错误定位其自身的表达，表明显性失活效应导致进行性神经变性，TBPH 突变失活也可见到。这些数据共同表明，果蝇 TDP-43 的功能障碍会引发一系列事件，导致功能丧失表型，从而受损的突触传递导致运动行为缺陷和神经元连接的渐进性解构，最终导致与年龄相关的神经变性。
Cytoplasmic accumulation and nuclear clearance of TDP-43 characterize familial and sporadic forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, suggesting that either loss or gain of TDP-43 function, or both, cause disease formation. Here we have systematically compared loss- and gain-of-function of Drosophila TDP-43, TAR DNA Binding Protein Homolog (TBPH), in synaptic function and morphology, motor control, and age-related neuronal survival. Both loss and gain of TBPH severely affect development and result in premature lethality. TBPH dysfunction caused impaired synaptic transmission at the larval neuromuscular junction (NMJ) and in the adult. Tissue-specific knockdown together with electrophysiological recordings at the larval NMJ also revealed that alterations of TBPH function predominantly affect pre-synaptic efficacy, suggesting that impaired pre-synaptic transmission is one of the earliest events in TDP-43-related pathogenesis. Prolonged loss and gain of TBPH in adults resulted in synaptic defects and age-related, progressive degeneration of neurons involved in motor control. Toxic gain of TBPH did not downregulate or mislocalize its own expression, indicating that a dominant-negative effect leads to progressive neurodegeneration also seen with mutational inactivation of TBPH. Together these data suggest that dysfunction of Drosophila TDP-43 triggers a cascade of events leading to loss-of-function phenotypes whereby impaired synaptic transmission results in defective motor behavior and progressive deconstruction of neuronal connections, ultimately causing age-related neurodegeneration.
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影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
38.1
作者：
Chen-Plotkin, Alice S.;Lee, Virginia M. -Y.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
2.3
作者：
Gitler, Aaron D.;Shorter, James
通讯作者：
Shorter, James
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
影响因子：
5.7
作者：
Da Cruz S;Cleveland DW
通讯作者：
Cleveland DW