title: 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 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.
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zlatic
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Heather Skye
authors.initials: HS
authors.lastname: Comstra
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Avanti
authors.initials: A
authors.lastname: Gokhale
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Petris
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Center for Social Translational Neuroscience, Emory University, Atlanta, GA 30322, USA. Electronic address: vfaunde@emory.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics*; D019295:Computational Biology; D000073840:Copper-Transporting ATPases; D006801:Humans; D007706:Menkes Kinky Hair Syndrome / Q000150:complications / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics*; D065886:Neurodevelopmental Disorders / Q000209:etiology / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
keywords: ATP7A; Copper; Menkes; Metal; Neurodegeneration