Institute of Biotechnology, Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
PLoS Genet. 2011 Feb 3;7(2):e1001288. doi: 10.1371/journal.pgen.1001288.
Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is caused by mutations in Valosin-containing protein (VCP), a hexameric AAA ATPase that participates in a variety of cellular processes such as protein degradation, organelle biogenesis, and cell-cycle regulation. To understand how VCP mutations cause IBMPFD, we have established a Drosophila model by overexpressing TER94 (the sole Drosophila VCP ortholog) carrying mutations analogous to those implicated in IBMPFD. Expression of these TER94 mutants in muscle and nervous systems causes tissue degeneration, recapitulating the pathogenic phenotypes in IBMPFD patients. TER94-induced neurodegenerative defects are enhanced by elevated expression of wild-type TER94, suggesting that the pathogenic alleles are dominant active mutations. This conclusion is further supported by the observation that TER94-induced neurodegenerative defects require the formation of hexamer complex, a prerequisite for a functional AAA ATPase. Surprisingly, while disruptions of the ubiquitin-proteasome system (UPS) and the ER-associated degradation (ERAD) have been implicated as causes for VCP-induced tissue degeneration, these processes are not significantly affected in our fly model. Instead, the neurodegenerative defect of TER94 mutants seems sensitive to the level of cellular ATP. We show that increasing cellular ATP by independent mechanisms could suppress the phenotypes of TER94 mutants. Conversely, decreasing cellular ATP would enhance the TER94 mutant phenotypes. Taken together, our analyses have defined the nature of IBMPFD-causing VCP mutations and made an unexpected link between cellular ATP level and IBMPFD pathogenesis.
包涵体肌病伴骨骼 Paget 病和额颞叶痴呆（IBMPFD）是由包含蛋白（VCP）基因突变引起的，VCP 是一种六聚体 AAA ATP 酶，参与多种细胞过程，如蛋白质降解、细胞器发生和细胞周期调控。为了了解 VCP 突变如何导致 IBMPFD，我们通过过表达携带类似于 IBMPFD 中涉及的突变的 TER94（唯一的果蝇 VCP 直系同源物）建立了一个果蝇模型。这些 TER94 突变体在肌肉和神经系统中的表达导致组织退化，重现了 IBMPFD 患者的致病表型。野生型 TER94 的表达水平升高增强了 TER94 诱导的神经退行性缺陷，表明致病等位基因是显性激活突变。这一结论进一步得到了以下观察结果的支持：TER94 诱导的神经退行性缺陷需要六聚体复合物的形成，这是功能性 AAA ATP 酶的前提。令人惊讶的是，虽然泛素-蛋白酶体系统（UPS）和内质网相关降解（ERAD）的破坏被认为是 VCP 诱导的组织退化的原因，但在我们的果蝇模型中，这些过程并没有受到显著影响。相反，TER94 突变体的神经退行性缺陷似乎对细胞内 ATP 水平敏感。我们表明，通过独立的机制增加细胞内 ATP 可以抑制 TER94 突变体的表型。相反，降低细胞内 ATP 会增强 TER94 突变体的表型。总之，我们的分析定义了导致 IBMPFD 的 VCP 突变的性质，并在细胞内 ATP 水平和 IBMPFD 发病机制之间建立了意想不到的联系。
