Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia
Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia
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DOI：
10.1073/pnas.0903134106
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发表时间：
2009-07-21
影响因子：
11.1
通讯作者：
Gao, Fen-Biao
中科院分区：
文献类型：
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作者：
Ahmad, S. Tariq;Sweeney, Sean T.;Gao, Fen-Biao
额颞叶痴呆 (FTD) 是 60 岁之前最常见的痴呆形式。 CHMP2B 编码运输所需的内体分选复合物 (ESCRT-III) 的一个组成部分，CHMP2B 中的罕见致病突变与 3 号染色体 (FTD3) 相关的 FTD 相关。 FTD3的动物模型尚未见报道，突变体CHMP2B在体内错误调节哪些信号通路尚不清楚。在这里，我们报告了 FTD3 果蝇模型的建立，并显示了突变体 CHMP2B 与 ESCRT 其他组件之间的遗传相互作用。通过无偏倚的全基因组筛选，我们鉴定了 29 个修饰位点，并发现 serpin5 (Spn5)（一种很大程度上未表征的丝氨酸蛋白酶抑制剂）可抑制果蝇眼中突变体 CHMP2B 诱导的黑化表型。我们还发现 Spn5 是 Toll 通路的负调节因子，并在细胞外发挥作用，可能是通过阻断 Toll 受体配体 Spaetzle 的蛋白水解激活。此外，Spn5 抑制突变体 CHMP2B 对 Toll 途径的激活。我们的研究结果确定 Spn5 是 Toll 途径和 CHMP2B 毒性的调节因子，并表明 Toll 途径是体内突变体 CHMP2B 错误调节的主要信号传导途径。该果蝇模型将有助于进一步剖析与 FTD 发病机制和治疗潜在相关的遗传途径。
Frontotemporal dementia (FTD) is the most common form of dementia before 60 years of age. Rare pathogenic mutations in CHMP2B, which encodes a component of the endosomal sorting complex required for transport (ESCRT-III), are associated with FTD linked to chromosome 3 (FTD3). Animal models of FTD3 have not yet been reported, and what signaling pathways are misregulated by mutant CHMP2B in vivo is unknown. Here we report the establishment of a Drosophila model of FTD3 and show the genetic interactions between mutant CHMP2B and other components of ESCRT. Through an unbiased genome-wide screen, we identified 29 modifier loci and found that serpin5 (Spn5), a largely uncharacterized serine protease inhibitor, suppresses the melanization phenotype induced by mutant CHMP2B in the fly eye. We also found that Spn5 is a negative regulator of the Toll pathway and functions extracellularly, likely by blocking the proteolytic activation of Spaetzle, the Toll receptor ligand. Moreover, Spn5 inhibited activation of the Toll pathway by mutant CHMP2B. Our findings identify Spn5 as a regulator of the Toll pathway and CHMP2B toxicity and show that the Toll pathway is a major signaling pathway misregulated by mutant CHMP2B in vivo. This fly model will be useful to further dissect genetic pathways that are potentially relevant to the pathogenesis and treatment of FTD.