Identification of ter94, Drosophila VCP, as a strong modulator of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS
Identification of ter94, Drosophila VCP, as a strong modulator of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS
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DOI：
10.1093/hmg/ddu055
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发表时间：
2014-07-01
影响因子：
3.5
通讯作者：
Yamaguchi, Masamitsu
中科院分区：
文献类型：
--
作者：
Azuma, Yumiko;Tokuda, Takahiko;Yamaguchi, Masamitsu
在人类中，在肉瘤融合（FUS）基因的突变已被确定在偶发性和家族性形式的肌萎缩性侧索硬化症（ALS）。Cabeza（Caz）是人FUS的果蝇直系同源物。以前，我们建立了果蝇模型ALS窝藏Caz敲低。这些果蝇在神经肌肉接头处的运动神经元（MN）中出现运动缺陷和解剖缺陷;这些表型表明，细胞核中生理FUS功能的丧失可导致MN变性，类似于FUS相关ALS中所见。在这里，我们的目的是探索分子，影响这些ALS样表型的果蝇模型与眼睛特异性和神经元特异性Caz敲低。我们研究了几个先前报道的ALS相关基因，发现Caz和ter 94（果蝇含人Valosin蛋白（VCP）的直系同源物）之间存在遗传联系。将ter 94的最强功能丧失等位基因与Caz敲低进行遗传杂交，强烈增强了由Caz敲低引起的粗糙眼表型和MN变性表型。相反，野生型ter 94在Caz敲低背景下的过表达显著抑制了这些表型。我们的数据表明，表达水平的果蝇VCP直系同源物显着修改的表型所造成的Caz敲低在任何一个方向，恶化或缓解。我们的研究结果表明，治疗剂，上调人类VCP的功能可以修改的致病过程，导致ALS的MN的变性。
In humans, mutations in the fused in sarcoma (FUS) gene have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). Cabeza (Caz) is the Drosophila ortholog of human FUS. Previously, we established Drosophila models of ALS harboring Caz-knockdown. These flies develop locomotive deficits and anatomical defects in motoneurons (MNs) at neuromuscular junctions; these phenotypes indicate that loss of physiological FUS functions in the nucleus can cause MN degeneration similar to that seen in FUS-related ALS. Here, we aimed to explore molecules that affect these ALS-like phenotypes of our Drosophila models with eye-specific and neuron-specific Caz-knockdown. We examined several previously reported ALS-related genes and found genetic links between Caz and ter94, the Drosophila ortholog of human Valosin-containing protein (VCP). Genetic crossing the strongest loss-of-function allele of ter94 with Caz-knockdown strongly enhanced the rough-eye phenotype and the MN-degeneration phenotype caused by Caz-knockdown. Conversely, the overexpression of wild-type ter94 in the background of Caz-knockdown remarkably suppressed those phenotypes. Our data demonstrated that expression levels of Drosophila VCP ortholog dramatically modified the phenotypes caused by Caz-knockdown in either direction, exacerbation or remission. Our results indicate that therapeutic agents that up-regulate the function of human VCP could modify the pathogenic processes that lead to the degeneration of MNs in ALS.