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

被引：132

作者：

Guthrie, Liam M. ^{[1
]}

Soma, Shivatheja ^{[2
]}

Yuan, Sai ^{[3
]}

Silva, Andres ^{[2
]}

Zulkifli, Mohammad ^{[2
]}

Snavely, Thomas C. ^{[2
]}

Greene, Hannah Faith ^{[2
]}

Nunez, Elyssa ^{[2
]}

Lynch, Brogan ^{[2
]}

De Ville, Courtney ^{[2
]}

Shanbhag, Vinit ^{[4
]}

Lopez, Franklin R. ^{[5
,6
]}

Acharya, Arjun ^{[2
]}

Petris, Michael J. ^{[4
]}

Kim, Byung-Eun ^{[3
]}

Gohil, Vishal M. ^{[2
]}

Sacchettini, James C. ^{[2
]}

机构：

[1] Texas A&M Hlth Sci Ctr, Dept Mol & Cellular Med, College Stn, TX 77843 USA

[2] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA

[3] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA

[4] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA

[5] Texas Vet Med Diagnost Labs, College Stn, TX 77843 USA

[6] Charles River Labs, Durham, NC 27703 USA

来源：

SCIENCE | 2020年 / 368卷 / 6491期

基金：

美国国家卫生研究院;

关键词：

COPPER TRANSPORT; OXIDASE DEFICIENCY; DRUG ELESCLOMOL; MURINE MODEL; DISEASE; MUTATIONS; BRAIN; ACQUISITION; MECHANISMS; OUTCOMES;

D O I：

10.1126/science.aaz8899

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：620 / +

页数：52

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