TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97.
TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97.
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DOI：
10.1523/jneurosci.5894-09.2010
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发表时间：
2010-06-02
期刊：
影响因子：
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通讯作者：
Taylor JP
中科院分区：
文献类型：
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作者：
Ritson GP;Custer SK;Freibaum BD;Guinto JB;Geffel D;Moore J;Tang W;Winton MJ;Neumann M;Trojanowski JQ;Lee VM;Forman MS;Taylor JP
包含体肌病伴佩吉特骨病和额颞叶痴呆（IBMPFD）是一种显性遗传性退行性疾病，由含缬氨肽蛋白（VCP）基因突变引起。VCP（小鼠p97，D. melanogaster和S.酿酒酵母）是高度保守的AAA+-ATP酶，其调节广泛的细胞过程。IBMPFD的发病机制尚不清楚。为了阐明致病机制，我们开发了一个果蝇模型的IBMPFD（突变VCP-related变性）。基于该模型的遗传筛选，我们确定了三种主要抑制变性的RNA结合蛋白;其中之一是TBPH，TAR DNA结合蛋白（TDP-43）的果蝇同源物。在这里，我们证明了VCP和TDP-43在遗传上相互作用，并且VCP中的致病突变导致TDP-43在体外和体内重新分布到细胞质中，复制了在IBMPFD和其他TDP-43蛋白病中观察到的主要病理。我们还证明，TDP-43从细胞核到细胞质的再分布足以诱导细胞毒性。此外，我们确定TDP-43中的致病突变促进了向细胞质的再分布，并增强了与VCP的遗传相互作用。总之，我们的结果表明，与VCP突变相关的变性部分是由细胞质中TDP-43的毒性功能获得介导的。我们认为这些发现可能与一系列广泛的TDP-43蛋白病的致病机制有关，包括额颞叶变性和肌萎缩侧索硬化。
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) is a dominantly inherited degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. VCP (p97 in mouse, TER94 in D. melanogaster, and CDC48 in S. cerevisiae) is a highly conserved AAA+-ATPase that regulates a wide array of cellular processes. The mechanism of IBMPFD pathogenesis is unknown. To elucidate the pathogenic mechanism, we developed and characterized a Drosophila model of IBMPFD (mutant VCP–related degeneration). Based on genetic screening of this model we identified three RNA-binding proteins that dominantly suppressed degeneration; one of these was TBPH, the Drosophila homolog of TAR DNA-binding protein (TDP-43). Here we demonstrate that VCP and TDP-43 interact genetically and that disease-causing mutations in VCP lead to redistribution of TDP-43 to the cytoplasm in vitro and in vivo, replicating the major pathology observed in IBMPFD and other TDP-43 proteinopathies. We also demonstrate that TDP-43 redistribution from the nucleus to the cytoplasm is sufficient to induce cytotoxicity. Furthermore, we determined that a pathogenic mutation in TDP-43 promotes redistribution to the cytoplasm and enhances the genetic interaction with VCP. Taken together, our results show that degeneration associated with VCP mutations is mediated in part by toxic gain-of-function of TDP-43 in the cytoplasm. We suggest that these findings are likely relevant to the pathogenic mechanism of a broad array of TDP-43 proteinopathies, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis.