Drosophila carrying pex3 or pex16 mutations are models of Zellweger syndrome that reflect its symptoms associated with the absence of peroxisomes.
Drosophila carrying pex3 or pex16 mutations are models of Zellweger syndrome that reflect its symptoms associated with the absence of peroxisomes.
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DOI：
10.1371/journal.pone.0022984
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Matsuno K
中科院分区：
文献类型：
--
作者：
Nakayama M;Sato H;Okuda T;Fujisawa N;Kono N;Arai H;Suzuki E;Umeda M;Ishikawa HO;Matsuno K
过氧化物酶体生物合成障碍（PBD）是目前难以治疗的多器官功能障碍性疾病，其起因于过氧化物酶体的生物合成缺陷。编码过氧化物酶的基因是已知的PBD的致病基因，其是过氧化物酶体生物发生或功能所必需的。人类过氧化物酶基因PEX 3或PEX 16是过氧化物酶体膜蛋白靶向所需的，它们的突变会导致齐薇格综合征（一类PBD）。对Zellweger综合征发病机制的认识不足阻碍了有效治疗方法的发展。在这里，我们开发了Zellweger综合征的潜在果蝇模型，其中果蝇pex3或pex16基因被破坏。在齐薇格综合征患者中发现，过氧化物酶体在纯合果蝇pex3突变体中没有观察到，这是幼虫致死的。然而，pex16纯合子缺乏其母亲的贡献是可行的，仍然保持了少量的过氧化物酶体样颗粒，即使PEX16是必不可少的过氧化物酶体在人类的生物合成。这些结果表明，pex3和pex16在果蝇过氧化物酶体生物合成的要求是不同的，和PEX16的直系同源物的作用可能有分歧的哺乳动物和果蝇。我们的齐薇格综合征模型苍蝇的表型，如幼虫致死的pex3，和减少的大小，缩短寿命，运动缺陷，和异常的脂质代谢的pex16，让人想起这种疾病的症状，虽然果蝇pex16突变体不重演婴儿死亡的齐薇格综合征。此外，pex16突变体表现出雄性特异性不育，导致从逮捕精母细胞成熟。pex16在体细胞胞囊细胞中表达，而在生殖细胞中不表达，在雄性生殖细胞的成熟过程中起重要作用，表明体细胞胞囊细胞中的过氧化物酶体依赖性信号可能有助于雄性生殖细胞的成熟进程。这些潜在的Zellweger综合征果蝇模型应该有助于我们了解其病理。
The peroxisome biogenesis disorders (PBDs) are currently difficult-to-treat multiple-organ dysfunction disorders that result from the defective biogenesis of peroxisomes. Genes encoding Peroxins, which are required for peroxisome biogenesis or functions, are known causative genes of PBDs. The human peroxin genes PEX3 or PEX16 are required for peroxisomal membrane protein targeting, and their mutations cause Zellweger syndrome, a class of PBDs. Lack of understanding about the pathogenesis of Zellweger syndrome has hindered the development of effective treatments. Here, we developed potential Drosophila models for Zellweger syndrome, in which the Drosophila pex3 or pex16 gene was disrupted. As found in Zellweger syndrome patients, peroxisomes were not observed in the homozygous Drosophila pex3 mutant, which was larval lethal. However, the pex16 homozygote lacking its maternal contribution was viable and still maintained a small number of peroxisome-like granules, even though PEX16 is essential for the biosynthesis of peroxisomes in humans. These results suggest that the requirements for pex3 and pex16 in peroxisome biosynthesis in Drosophila are different, and the role of PEX16 orthologs may have diverged between mammals and Drosophila. The phenotypes of our Zellweger syndrome model flies, such as larval lethality in pex3, and reduced size, shortened longevity, locomotion defects, and abnormal lipid metabolisms in pex16, were reminiscent of symptoms of this disorder, although the Drosophila pex16 mutant does not recapitulate the infant death of Zellweger syndrome. Furthermore, pex16 mutants showed male-specific sterility that resulted from the arrest of spermatocyte maturation. pex16 expressed in somatic cyst cells but not germline cells had an essential role in the maturation of male germline cells, suggesting that peroxisome-dependent signals in somatic cyst cells could contribute to the progression of male germ-cell maturation. These potential Drosophila models for Zellweger syndrome should contribute to our understanding of its pathology.
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影响因子：
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