PNAS:遗传学研究新发现!或可用于治疗线粒体疾病
2016/08/24
近日,一项发表在《美国国家科学院院刊》 (PNAS)上的研究揭示:密苏里大学的研究者成功使用异质体(heteroplasmy)创造出胚胎,证实了父系线粒体和母系线粒体的存在,该研究或可进一步揭示父系DNA是否会导致人类线粒体疾病。


线粒体疾病:一种呈母系遗传的DNA缺陷

一般而言,父母通过生育将自己的基因传递给孩子,大部分的DNA是父母各占一半。然而,有一种特殊类型的DNA——线粒体DNA,它是只通过母系一脉传递的遗传基因,男性也能从母亲那里继承“线粒体DNA”,却无法将它遗传给自己的后代。

线粒体疾病是指线粒体DNA缺陷,即线粒体DNA重复、缺失或突变造成的疾病。位于线粒体的致病基因,呈母性遗传方式,后代中无论生男生女均可患病。

PNAS:创造出了含父系线粒体DNA的胚胎

近日,一项发表在《美国国家科学院院刊》 (PNAS)上的研究揭示:密苏里大学的研究者成功使用异质体(heteroplasmy)创造出胚胎,并从中证实了父系线粒体和母系线粒体的存在。

密苏里大学生殖生理学教授Peter Sutovsky以及该校农业食品资源学院的博士研究生Won-Hee Song是该研究的作者,他们已经找到一种方法来防止猪胚胎里父系线粒体DNA的丢失,即使用异质体创造出胚胎。

找到了父系线粒体DNA丢失的机制

在他们的研究中,Sutovsky教授和Song识别了两个独立的泛素结合(ubiquitin-binding)的蛋白质,依次叫做SQSTM1和缬酪肽包含蛋白(VCP)。在胚胎它们负责消除精子中的父系线粒体及其遗传物质。

而后,他们和同事尝试分别抑制SQSTM1和VCP,发现即使有一种蛋白质丧失劳动能力,其他蛋白仍然可以消除受精卵里的父系线粒体。 但当两种蛋白质同时被抑制时,父系线粒体没有被删除,仍然存在胚胎中。

有望探索出线粒体疾病的治疗方法

据了解,这是生物学上一项重要的创新,科学家有望探索出人类线粒体疾病的治疗方法以及认知家畜线粒体遗传的重要性。

在美国,每年有多达4000名新生儿伴有某种形式的线粒体疾病,包括生长缓慢、肌肉生长不协调、学习障碍和心脏病等。

过往的研究证实:线粒体疾病可能是由于异质体导致,也可能是父系和母系线粒体DNA在细胞中生长过程中的相关作用导致。

Sutovsky教授团队已经成功地在猪胚胎里创造了异质体,并发现了导致胚胎中线粒体DNA删除的机制,可进一步研究父系DNA是否会导致人类线粒体疾病,从而创建预防或减少线粒体疾病的新型疗法。

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  • Autophagy and ubiquitin–proteasome system contribute to sperm mitophagy after mammalian fertilization

    Maternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochondria after fertilization. However, it is not clear how the 26S proteasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mammalian sperm mitophagy. We found that the SQSTM1, but not GABARAP or LC3, associated with sperm mitochondria after fertilization in pig and rhesus monkey zygotes. Three sperm mitochondrial proteins copurified with the recombinant, ubiquitin-associated domain of SQSTM1. The accumulation of GABARAP-containing protein aggregates was observed in the vicinity of sperm mitochondrial sheaths in the zygotes and increased in the embryos treated with proteasomal inhibitor MG132, in which intact sperm mitochondrial sheaths were observed. Pharmacological inhibition of VCP significantly delayed the process of sperm mitophagy and completely prevented it when combined with microinjection of autophagy-targeting antibodies specific to SQSTM1 and/or GABARAP. Sperm mitophagy in higher mammals thus relies on a combined action of SQSTM1-dependent autophagy and VCP-mediated dislocation and presentation of ubiquitinated sperm mitochondrial proteins to the 26S proteasome, explaining how the whole sperm mitochondria are degraded inside the fertilized mammalian oocytes by a protein recycling system involved in degradation of single protein molecules.

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