Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice

doi:10.1126/science.aaz8899

GSTDTAP > 气候变化

DOI	10.1126/science.aaz8899
	Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice
	Liam M. Guthrie; Shivatheja Soma; Sai Yuan; Andres Silva; Mohammad Zulkifli; Thomas C. Snavely; Hannah Faith Greene; Elyssa Nunez; Brogan Lynch; Courtney De Ville; Vinit Shanbhag; Franklin R. Lopez; Arjun Acharya; Michael J. Petris; Byung-Eun Kim; Vishal M. Gohil; James C. Sacchettini
	2020-05-08
发表期刊	Science
出版年	2020
英文摘要	Menkes disease results from loss-of-function mutations in the P-type copper-transporting adenosine triphosphatase ATP7A. Children diagnosed with Menkes present with connective tissue abnormalities and neurodegenerative changes that result in death caused by severe copper deficiency, typically before 3 years of age. In the brain, lack of copper impairs cytochrome c oxidase (complex IV) in the electron transport chain, which leads to progressive neurological injury in Menkes patients. No treatment exists for Menkes disease because of the difficulty in supplying the brain with copper using traditional hydrophilic copper complexes such as copper histidine. Guthrie et al. developed a treatment involving the drug elesclomol that successfully alleviated disease symptoms in a mouse model of Menkes disease (see the Perspective by Lutsenko). Science , this issue p. [620][1]; see also p. [584][2] Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse—a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency. [1]: /lookup/doi/10.1126/science.aaz8899 [2]: /lookup/doi/10.1126/science.abb6662
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/249807
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Liam M. Guthrie,Shivatheja Soma,Sai Yuan,et al. Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice[J]. Science,2020.
APA	Liam M. Guthrie.,Shivatheja Soma.,Sai Yuan.,Andres Silva.,Mohammad Zulkifli.,...&James C. Sacchettini.(2020).Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice.Science.
MLA	Liam M. Guthrie,et al."Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice".Science (2020).