The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease

Nadine Bakkar, Alexander Starr, Benjamin E. Rabichow, Ileana Lorenzini, Zachary T. McEachin, Robert Kraft, Matthew Chaung, Sam Macklin-Isquierdo, Taylor Wingfield, Briggs Carhart, Nathan Zahler, Wen Hsuan Chang, Gary J. Bassell, Alexandre Betourne, Nicholas Boulis, Samuel V. Alworth, Justin K. Ichida, Paul R. August, Daniela C. Zarnescu, Rita SattlerRobert Bowser

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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 ATP7AM1311V 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.

Original languageEnglish (US)
Article number105228
JournalNeurobiology of Disease
StatePublished - Feb 2021


  • ATP7A
  • Amyotrophic lateral sclerosis
  • Copper toxicity
  • Copper transport
  • Intracellular transport
  • iPSC derived motor neurons

ASJC Scopus subject areas

  • Neurology


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