Molecular basis of neurodegeneration and neurodevelopmental defects in Menkes disease
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.
References (91)
Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse
Dev. Biol.
(2005)ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis
Mol. Cell. Neurosci.
(2007)Congenital abnormalities in Japanese patients with Menkes disease
Brain Dev.
(2012)Distinct and overlapping roles for AP-1 and GGAs revealed by the “knocksideways” system
Curr. Biol.
(2012)Lysyl oxidase is required for vascular and diaphragmatic development in mice
J. Biol. Chem.
(2003)Catecholamine biosynthesis and the activity of a number of copper-dependent enzymes in the copper deficient mottled mouse mutants
Comp. Biochem. Physiol. C
(1977)Electron microscopic study on the homozygote (Ml/Ml) of the macular mutant mouse
Brain Dev.
(1990)Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy
Am. J. Hum. Genet.
(2010)A conditional mutation affecting localization of the Menkes disease copper ATPase. Suppression by copper supplementation
J. Biol. Chem.
(2002)Increase of flux control of cytochrome c oxidase in copper-deficient mottled brindled mice
J. Biol. Chem.
(1996)
Nna1 mediates Purkinje cell dendritic development via lysyl oxidase propeptide and NF-kappaB signaling
Neuron
Cytochrome c oxidase deficiency in Menkes kinky hair disease
Brain Dev.
Lysyl oxidase is essential for normal development and function of the respiratory system and for the integrity of elastic and collagen fibers in various tissues
Am. J. Pathol.
Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B
J. Biol. Chem.
Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation
Curr. Biol.
Changes of copper level and cytochrome c oxidase activity in the macular mouse with age
Brain Dev.
ATP7A determines a hierarchy of copper metabolism essential for notochord development
Cell Metab.
Kinky hair disease: twenty five years later
Brain Dev.
Molecular diagnosis of Menkes disease: genotype–phenotype correlation
Biochimie
Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment
Neuroscience
Light and electron microscopic study on cerebellar cortex of macular mutant mouse as a model of Menkes kinky hair disease
Brain Dev.
Endosomal trafficking of the Menkes copper ATPase ATP7A is mediated by vesicles containing the Rab7 and Rab5 GTPase proteins
Exp. Cell Res.
Menkes disease and infantile epilepsy
Brain Dev.
Polydendritic Purkinje cells in X-chromosome linked copper malabsorption: a Golgi study
Brain Res.
Molecular mechanisms of resistance and toxicity associated with platinating agents
Cancer Treat. Rev.
Depletion of brain mitochondria cytochrome oxidase in the mottled mouse mutant
Exp. Neurol.
Neurodegeneration in the animal model of Menkes' disease involves Bcl-2-linked apoptosis
Neuroscience
Copper imbalances in ruminants and humans: unexpected common ground
Adv. Nutr.
Menkes disease
J. Med. Genet.
Neuropathology of Menkes' disease
Dev. Med. Child Neurol.
Clinical, cellular, and neuropathological consequences of AP1S2 mutations: further delineation of a recognizable X-linked mental retardation syndrome
Hum. Mutat.
Peptidylglycine alpha-amidating monooxygenase and copper: a gene–nutrient interaction critical to nervous system function
J. Neurosci. Res.
Identification of hepatic copper-binding proteins from tilapia by column chromatography with proteomic approaches
Metallomics
Copper-dependent co-internalization of the prion protein and glypican-1
J. Neurochem.
Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse
Am. J. Hum. Genet.
The many clinical faces of cytochrome c oxidase deficiency
Adv. Exp. Med. Biol.
l-Threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model
Ann. Neurol.
Haploinsufficiency in peptidylglycine alpha-amidating monooxygenase leads to altered synaptic transmission in the amygdala and impaired emotional responses
J. Neurosci.
Copper signaling in the mammalian nervous system: synaptic effects
J. Neurosci. Res.
Peptidylglycine alpha-amidating monooxygenase heterozygosity alters brain copper handling with region specificity
J. Neurochem.
Pam heterozygous mice reveal essential role for Cu in amygdalar behavioral and synaptic function
Ann. N. Y. Acad. Sci.
Trichopoliodystrophy. II. Pathological changes in skeletal muscle and nervous system
Arch. Neurol.
Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity
J. Clin. Oncol.
A survey of Japanese patients with Menkes disease from 1990 to 2003: incidence and early signs before typical symptomatic onset, pointing the way to earlier diagnosis
J. Inherit. Metab. Dis.
Fine structure of the cerebellar cortex in Menkes kinky-hair disease. X-chromosome-linked copper malabsorption
Arch. Neurol.
Cited by (35)
Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype
2024, European Journal of Medical GeneticsThe elements of life: A biocentric tour of the periodic table
2023, Advances in Microbial PhysiologyReprint of: Elemental dysregulation in psychotic spectrum disorders: A review and research synthesis
2022, Schizophrenia ResearchElemental dysregulation in psychotic spectrum disorders: A review and research synthesis
2021, Schizophrenia ResearchCitation Excerpt :Additionally, it is imperative to perform longitudinal studies examining the relation between PSD and exposures prenatally, in childhood, and adolescence. Deficiencies in nutritive elements are associated with a myriad of unfavorable health outcomes including adverse neurodevelopment and likely also PSD, although direct evidence is limited (Black, 1998; Claus Henn et al., 2010; Susser et al., 1996; Zlatic et al., 2015). Nutritive element excess in relation to psychiatric outcomes has received even less attention.
Rare Genetic Diseases: Nature's Experiments on Human Development
2020, iScienceCitation Excerpt :These enzymes play major roles in mitochondrial respiration, neurotransmitter, and neuropeptide biosynthesis respectively. We termed this enzymatic model of neurological phenotypes the oligoenzymatic hypothesis, which we consider insufficient to explain Menkes neuropathology (Kaler, 2011; Menkes, 1999; Zlatic et al., 2015). In fact, the interactome of the Menkes ATPase ATP7A and the proteome of ATP7A null cells are enriched in gene products involved in neurodegenerative and neurodevelopmental diseases, suggesting a larger complexity to the pathogenesis mechanisms in Menkes neurological disease (Comstra et al., 2017; Hartwig et al., 2019; Zlatic et al., 2018).
Trafficking mechanisms of P-type ATPase copper transporters
2019, Current Opinion in Cell Biology