Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease

NEUROBIOLOGY OF DISEASE

卷:81

Article

Zlatic, Stephanie¹  Comstra, Heather Skye¹  Gokhale, Avanti¹  Petris, Michael J.²  Faundez, Victor^1,3 

[1] Emory Univ, Dept Cell Biol, Atlanta, GA 30322 USA

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

[3] Emory Univ, Ctr Social Translat Neurosci, Atlanta, GA 30322 USA

关键词: Copper;    Metal;    Menkes;    ATP7A;    Neurodegeneration;   

DOI  :  10.1016/j.nbd.2014.12.024

来源: Elsevier

【 摘 要 】

ATP7A mutations impair copper metabolism resulting in three distinct genetic disorders in humans. These diseases are characterized by neurological phenotypes ranging from intellectual disability to neurodegeneration. Severe ATP7A loss-of-function alleles trigger Menkes disease, a copper deficiency condition where systemic and neurodegenerative phenotypes dominate clinical outcomes. The pathogenesis of these manifestations has been attributed to the hypoactivity of a limited number of copper-dependent enzymes, a hypothesis that we refer as the oligoenzymatic pathogenic hypothesis. This hypothesis, which has dominated the field for 25 years, only explains some systemic Menkes phenotypes. However, we argue that this hypothesis does not fully account for the Menkes neurodegeneration or neurodevelopmental phenotypes. Here, we propose revisions of the oligoenzymatic hypothesis that could illuminate the pathogenesis of Menkes neurodegeneration and neurodevelopmental defects through unsuspected overlap with other neurological conditions including Parkinson's, intellectual disability, and schizophrenia. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

Free