Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease

Abstract

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 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.

Neuroimaging Changes in Menkes Disease, Part 2

“…5,6 Failure to thrive, hypothermia, hypotonia, impaired cognitive development, and relentless regression of developmental milestones highlight and reflect the primary involvement of the central nervous system. The scarce neuropathologic findings, both at gross and histology examination, are overtly dominated by neurodegeneration.…”

Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees

“…UCHL1/PARK5 and QPRT protein expression modifications were even more pronounced than expression changes in two factors known to require or interact with ATP7A, LOX and GLRX (Fig. 3A–B) (Lim et al, 2006; Singleton et al, 2010; Zlatic et al, 2015). We further confirmed the changes in UCHL1/PARK5 and QPRT protein expression measuring their transcripts, which increase 6–8-fold in ATP7A mutant cells (Fig.…”

“…These phenotypes have been attributed to the reduced activity of cuproenzymes involved in extracellular matrix and melanin synthesis. In contrast, the pathogenesis of Menkes neurodevelopmental and neurodegeneration symptoms is still unknown (Zlatic et al, 2015). Additionally, in vitro cultured Menkes disease cells mimic the systemic cellular consequences of noxious copper accumulation similar to those that characterize Wilson disease, a disorder that includes psychiatric and Parkinsonian symptomatology (Bandmann et al, 2015; Davies et al, 2016; Dusek et al, 2015; Kaler, 2011).…”

“…It has been suggested that the source of Menkes disease brain symptoms result from decreased enzymatic activity in cuproenzymes necessary for the synthesis of neurotransmitters, neuropeptides, and mitochondrial respiration (Kaler, 2011). However, Menkes neurodevelopmental and neurodegeneration mechanisms are likely to involve factors other than cuproenzymes as suggested by the ATP7A interactome that enriches neurodevelopmental disorder and neurodegeneration causative genes (Comstra et al, 2017; Zlatic et al, 2015). …”

Metals and neurodegeneration

“…Further observations on NBIA come from the study Santambrogio et al (2015), which takes advantage of primary skin fibroblasts and neurons reprogramed from fibroblasts of patients harboring mutations in the PANK2 gene, and describes anomalies in redox balance, in iron homeostasis, and in bioenergetics. Zlatic et al (2015) reviewed the molecular basis of neurodevelopmental and neurodegenerative defects in Menkes disease, a rare condition caused by mutations in the trans-Golgi copper-transporter P-ATPase, ATP7A. This article not only summarizes state-of-the-art knowledge about this disorder, but also challenges the predominant mechanistic hypothesis of pathogenesis – the oligoenzymatic hypothesis – providing a revised and more comprehensive version.…”