Elsevier

Neurobiology of Disease

Volume 81, September 2015, Pages 154-161
Neurobiology of Disease

Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease

https://doi.org/10.1016/j.nbd.2014.12.024Get rights and content

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 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.

Introduction

Genetic defects in the trans-Golgi copper-transporter P-ATPase, ATP7A, cause three distinct X-linked recessive disorders: occipital horn syndrome (OMIM 304150), spinal muscular atrophy, distal, X-linked 3 (SMAX3, OMIM 300489), and Menkes disease (OMIM 309400) (Kaler, 2011). More than 350 different mutations affecting the ATP7A gene have been described (Moller et al., 2009, Tumer, 2013). These disease-associated mutations are quite heterogeneous in their genomic location and the type of DNA defect and, unlike other genetic disorders, there are no recurrent genetic defects that account for a significant number of cases (Tumer, 2013). Milder mutations in ATP7A result in occipital horn syndrome in which connective tissue and bone abnormalities predominate and patients lack the severe neurological phenotypes of Menkes disease (Das et al., 1995, Kaler et al., 1994). Yet another ATP7A-related disease is SMAX3, in which missense mutations not severe enough to perturbate systemic copper status cause a non-demyelinating spinomuscular atrophy (Kennerson et al., 2010, Takata et al., 2004). At the far end of the spectrum is Menkes disease in which the most severe loss-of-function mutations result in a multisystemic metabolic disorder of copper deficiency. Here we focus in Menkes disease, first described in 1962 in a single family that in two generations accumulated five male infants affected by intellectual disability, failure to thrive, prominent neurological manifestations, neurodegeneration, epilepsy, and ‘peculiar white hair’ (Menkes et al., 1962). Menkes disease is a rare affliction with an incidence of 1/140,000 to 1/300,000 (Gu et al., 2005, Tonnesen et al., 1991). Although this disease has been studied for more than 50 years and its metabolic foundations are known (Kaler, 2011, Menkes, 1988), we contend that the pathogenic mechanisms underlying neurodegeneration and neurodevelopmental defects remain poorly understood. In this review, we explore neuropathogenic hypotheses and argue that some of the classic ideas invoked to explain Menkes disease phenotypes, although logical, remain speculative and inadequate. We propose an updated modified hypothesis in light of newer findings to account for the neurological manifestations of ATP7A loss-of-function mutations.

Our interest in Menkes disease pathogenesis extends beyond this genetic disorder. Because the neurological symptoms associated with Menkes disease are common to other neuropsychiatric disorders of childhood and adulthood (Kaler, 2011, Menkes, 1988), it is increasingly recognized that Menkes disease studies may shed light into the mechanisms of other prevalent disorders. Menkes pathogenesis mechanisms can thus be a tool to understand: a) neuronal mechanisms where copper participates either as a micronutrient or a toxicant; b) pathways of neuronal cell death triggered by altered metabolic homeostasis; c) mechanisms that cells use to respond to neurotoxic anticancer agents such as platinum compounds, which bind to ATP7A (Gregg et al., 1992, Inesi et al., 2014, Liu et al., 2012, Rabik and Dolan, 2007); d) regulatory mechanisms of key receptors and channels involved in neurotransmission and neurodegeneration. These include N-methyl-d-aspartate (NMDA) receptors, voltage-gated calcium channels, APP, and the prion protein to mention few (Gaier et al., 2013a, Hung et al., 2010, Kaler, 2011, Stys et al., 2012); and e) mechanisms of development that could account for defective cell positioning observed in Menkes gray matter (Mendelsohn et al., 2006).

Section snippets

Clinical and pathological characteristics of Menkes disease

Menkes disease manifests itself between two to twelve months after birth with hypotonia, failure to thrive, focal and generalized seizures, impaired cognitive development, and brain atrophy at the expense of the gray and white matter. Hypotonia at birth evolves into spastic paresis. Systemic features associated with the disease include the characteristic hypopigmented “kinky hair”, which at the microscopic level reveals pili torti (twisted hairs), monilethrix (beaded hairs) and thickening or

Menkes disease neuropathology

Menkes is characterized by widespread atrophy of the gray and white matter. At the light microscopic level there is focal degeneration that extends to all layers of the cerebral cortex. Neuronal cell loss is most pronounced in the cerebral cortex but affects the hippocampus, striatum, hypothalamus and thalamus to a variable degree. In the cerebral cortex neuronal cell loss is commonly associated with astrocytosis (Barnard et al., 1978, Ghatak et al., 1972, Hirano et al., 1977, Menkes et al.,

Cell biology of Menkes disease

Menkes disease is the product of either absent or impaired ATP7A copper pump activity and/or improper subcellular localization (Kaler, 2011, Kim and Petris, 2007, Kim et al., 2002, Kim et al., 2003). The consequence of such defects at the cellular level is an impaired intraluminal Golgi or cytoplasmic copper homeostasis. At low extracellular copper concentrations, wild type ATP7A resides in the trans-Golgi network (TGN) where it pumps copper into the lumen of the trans-Golgi network as a

The oligoenzymatic pathogenic hypothesis of Menkes disease

Is the Menkes neuropathology due to nutritional copper depletion or an intrinsic lack of ATP7A in neurons? Menkes disease neuropathology is recapitulated by conditional deletion of ATP7A in the gut (Wang et al., 2012). This powerful evidence argues that copper depletion in the brain leads to Menkes neuropathology. Menkes neurological manifestations have been ascribed to five enzymes expressed in the brain that require copper for their function. Presently, these enzymes include mitochondrial

Proposed revisions to the oligoenzymatic hypothesis

The oligoenzymatic hypothesis seeks to link ATP7A copper-sensitive targets to disease manifestations. However, the oligoenzymatic hypothesis alone may not adequately explain neurodegeneration and neurodevelopmental phenotypes due to the paucity of copper-sensitive targets that it considers. We propose that simply considering ontological categories to which these few enzymes belong can enhance the oligoenzymatic hypothesis. Cytochrome C oxidase, PAM, SOD3, DBH, LOX, and tyrosinase are part of

Conclusions

Menkes neurological and neurodevelopmental manifestations have been attributed to defects in a select group of enzymes that require copper. However, knowledge gained from genetic experiments affecting these enzymes indicates that in isolation they are insufficient to account for the neurological manifestations in Menkes. We propose a revised version of the oligoenzymatic hypothesis that includes all molecules in the copper-binding ontological category and molecules that may be sensitive to

Conflict of interest

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare no conflict of interest.

Acknowledgments

This work was supported by grants from the National Institutes of Health GM077569, and R21NS088503 to VF and DK093386 to MJP.

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