In Vivo Modeling of the Pathogenic Effect of Copper Transporter Mutations That Cause Menkes and Wilson Diseases, Motor Neuropathy, and Susceptibility to Alzheimer's Disease

Abstract

Copper is an essential biometal, and several inherited diseases are directly associated with a disruption to normal copper homeostasis. The best characterized are the copper deficiency and toxicity disorders Menkes and Wilson diseases caused by mutations in the p-type Cu-ATPase genes and, respectively. Missense mutations in the C-terminal portion of have also been shown to cause distal motor neuropathy, whereas polymorphisms in are associated with increased risk of Alzheimer's disease. We have generated a single, model for studying multiple pathogenic mutations in ATP7 proteins using, which has a single orthologue of ATP7A and ATP7B. Four pathogenic mutations and two mutations were introduced into a genomic rescue construct containing an in-frame C-terminal GFP tag. Analysis of the wild type transgene confirmed that ATP7 is expressed at the basolateral membrane of larval midgut copper cells and that the transgene can rescue a normally early lethal deletion allele to adulthood. Analysis of the transgenes containing pathogenic mutations showed that the function of ATP7 was affected, to varying degrees, by all six of the mutations investigated in this study. Of particular interest, the ATP7B Alzheimer's disease susceptibility allele was found, for the first time, to be a loss of function allele. This system allows us to assess the severity of individual/ mutations in an invariant genetic background and has the potential to be used to screen for therapeutic compounds able to restore function to faulty copper transport proteins.

Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease

“…(45) Of particular interest, the ATP7B-K832R and -R952K polymorphisms appear to be Alzheimer disease susceptibility alleles. (46,47) If this association proves to be correct, some forms of dementia may be late symptoms of WD. These observations raise several important questions regarding the initial and long-term management of patients.…”

“…A subgroup of patients with Alzheimer disease has some evidence for copper toxicity . Of particular interest, the ATP7B ‐K832R and ‐R952K polymorphisms appear to be Alzheimer disease susceptibility alleles . If this association proves to be correct, some forms of dementia may be late symptoms of WD.…”

Alzheimer’s disease: How metal ions define β-amyloid function

“…Currently, the redox activity of Aβ has been viewed as a gain of toxic function. However, redox activity may also be part of the normal function of Aβ as a cross-membrane metal transport peptide, because Aβ serves a normal role in synaptic transmission [466], and reduction to Cu(I) and Fe(II) is a common feature of cross-membrane metal transport[3] [262]. Additionally, the redox activity can be anti-oxidant in its nature, depending on the exact half potential and the presence of other redox active molecules such as ascorbate: Indeed, Aβ can protect against copper and iron induced oxidative stress [167][467] [468].…”

Is copper a new target to counteract the progression of chronic diseases?

“…45 Although most mutations in the ATP7A gene cause Menkes' disease, some missense mutations induce a weaker disease called Occipital Horn Syndrome. 46,47 Patients with Occipital Horn Syndrome suffer from connective tissue abnormalities as with Menkes' disease patients, but do not usually present neurological symptoms and have a considerably longer average lifespan. 47 Genetic Wilson's disease is an autosomal recessive disorder characterized by a lack of fully functional ATP7B protein, thus Cu accumulation in the liver and subsequently in the brain and kidney occurs.…”

“…46,47 Patients with Occipital Horn Syndrome suffer from connective tissue abnormalities as with Menkes' disease patients, but do not usually present neurological symptoms and have a considerably longer average lifespan. 47 Genetic Wilson's disease is an autosomal recessive disorder characterized by a lack of fully functional ATP7B protein, thus Cu accumulation in the liver and subsequently in the brain and kidney occurs. In addition, Wilson's disease patients typically develop severe liver disease and may present additional neurological symptoms as well.…”