1. The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease.
- Author
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Bakkar N, Starr A, Rabichow BE, Lorenzini I, McEachin ZT, Kraft R, Chaung M, Macklin-Isquierdo S, Wingfield T, Carhart B, Zahler N, Chang WH, Bassell GJ, Betourne A, Boulis N, Alworth SV, Ichida JK, August PR, Zarnescu DC, Sattler R, and Bowser R
- Subjects
- Animals, Animals, Genetically Modified, Animals, Newborn, Cells, Cultured, Copper pharmacology, Copper therapeutic use, Dose-Response Relationship, Drug, Drosophila, Genetic Variation drug effects, HeLa Cells, Homeostasis drug effects, Homeostasis physiology, Humans, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells metabolism, Mice, Motor Neuron Disease drug therapy, Protein Transport drug effects, Protein Transport physiology, Copper metabolism, Copper-Transporting ATPases genetics, Copper-Transporting ATPases metabolism, Genetic Variation physiology, Motor Neuron Disease genetics, Motor Neuron Disease metabolism
- Abstract
Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7A
M1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V . Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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