Overexpression of ter94, Drosophila VCP, improves motor neuron degeneration induced by knockdown of TBPH, Drosophila TDP-43.
Overexpression of ter94, Drosophila VCP, improves motor neuron degeneration induced by knockdown of TBPH, Drosophila TDP-43.
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发表时间：
2018
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通讯作者：
Y. Kushimura;T. Tokuda;Y. Azuma;I. Yamamoto;I. Mizuta;T. Mizuno;M. Nakagawa;M. Ueyama;Y. Nagai;H. Yoshida;M. Yamaguchi
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作者：
Y. Kushimura;T. Tokuda;Y. Azuma;I. Yamamoto;I. Mizuta;T. Mizuno;M. Nakagawa;M. Ueyama;Y. Nagai;H. Yoshida;M. Yamaguchi
肌萎缩性侧索硬化症（ALS）是一种以运动神经元变性为特征的快速进展性神经退行性疾病，最终在发病后2-5年内导致完全瘫痪和死亡。ALS的主要病理标志之一是含有TAR dna结合蛋白43 （TDP-43）的包涵体的异常积累。TDP-43通常存在于细胞核中，但在ALS中，它以包涵体的形式存在于细胞质中，也存在于细胞核中。核TDP-43功能的丧失可能导致神经退行性变。TBPH是人类TDP-43的果蝇同源基因。在本研究中，我们证实了携带TBPH敲低的果蝇模型由于其核功能的丧失而产生运动神经元（MNs）的运动缺陷和变性，再现了人类ALS表型。我们之前提出ter94，人类含缬氨酸蛋白（VCP）的果蝇同源物，是一种由敲低Caz（人类FUS的果蝇同源物）诱导的MNs变性的调节剂。在这项研究中，为了确定VCP对tdp -43相关的ALS致病过程的影响，我们研究了TBPH和ter94之间的遗传相互作用。ter94过表达抑制TBPH敲低引起的复眼变性，抑制神经元特异性TBPH敲低引起的运动功能障碍、MN末端变性等病态表型。进一步的免疫细胞化学分析显示，这种抑制是由细胞质错误定位的TBPH恢复到细胞核引起的。与这些观察结果一致，ter94的功能缺失突变增强了TBPH敲低引起的复眼变性，并部分增强了TBPH敲低引起的运动功能障碍。我们的数据表明，ter94的表达水平影响TBPH敲低引起的表型，并且表明上调人VCP功能的试剂可以改变由TDP-43错位引起的ALS的MN变性。
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the motor neuron degeneration that eventually leads to complete paralysis and death within 2-5 years after disease onset. One of the major pathological hallmark of ALS is abnormal accumulation of inclusions containing TAR DNA-binding protein-43 (TDP-43). TDP-43 is normally found in the nucleus, but in ALS, it localizes in the cytoplasm as inclusions as well as in the nucleus. Loss of nuclear TDP-43 functions likely contributes to neurodegeneration. TBPH is the Drosophila ortholog of human TDP-43. In the present study, we confirmed that Drosophila models harboring TBPH knockdown develop locomotive deficits and degeneration of motoneurons (MNs) due to loss of its nuclear functions, recapitulating the human ALS phenotypes. We previously suggested that ter94, the Drosophila ortholog of human Valosin-containing protein (VCP), is a modulator of degeneration in MNs induced by knockdown of Caz, the Drosophila ortholog of human FUS. In this study, to determine the effects of VCP on TDP-43-assosiated ALS pathogenic processes, we examined genetic interactions between TBPH and ter94. Overexpression of ter94 suppressed the compound eye degeneration caused by TBPH knockdown and suppressed the morbid phenotypes caused by neuron-specific TBPH knockdown, such as locomotive dysfunction and degeneration of MN terminals. Further immunocytochemical analyses revealed that the suppression is caused by restoring the cytoplasmically mislocalized TBPH back to the nucleus. In consistent with these observations, a loss-of-function mutation of ter94 enhanced the compound eye degeneration caused by TBPH knockdown, and partially enhanced the locomotive dysfunction caused by TBPH knockdown. Our data demonstrated that expression levels of ter94 influenced the phenotypes caused by TBPH knockdown, and indicate that reagents that up-regulate the function of human VCP could modify MN degeneration in ALS caused by TDP-43 mislocalization.