Zlatic Stephanie, Comstra Heather Skye, Gokhale Avanti, Petris Michael J, Faundez Victor
Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
Neurobiol Dis. 2015 Sep;81:154-61. doi: 10.1016/j.nbd.2014.12.024. Epub 2015 Jan 10.
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.
ATP7A突变会损害铜代谢，导致人类出现三种不同的遗传疾病。这些疾病的特征是具有从智力残疾到神经退行性变等一系列神经学表型。严重的ATP7A功能丧失等位基因会引发门克斯病，这是一种铜缺乏症，全身和神经退行性表型主导临床结果。这些表现的发病机制归因于有限数量的铜依赖性酶的活性低下，我们将这一假说称为寡酶致病假说。这一在该领域主导了25年的假说，仅解释了一些全身性门克斯病表型。然而，我们认为该假说并不能完全解释门克斯病的神经退行性变或神经发育表型。在此，我们提出对寡酶假说的修订，这可能通过与帕金森病、智力残疾和精神分裂症等其他神经疾病意想不到的重叠，阐明门克斯病神经退行性变和神经发育缺陷的发病机制。
