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

Bakkara N, Starra A, Rabichowa BE, Lorenzini I, McEachin ZT, Kraft R, Chaung M, Macklin-Isquierdo M, Wingfield T, Carhart B, Zahler N, ChangW-H, Bassell GJ, Betourne A, Boulis N, Alworth SV, Ichida JK, August PR, Zarnescu DC, Sattler R, Bowser R.

Neurobiology of Disease, 2021


Disruption in copper homeostatis can cause a number of neurodevelopmental disorders such as Wilson's disease and Menkes disease.  This study investigated if the M1311V variation found in an ALS patient potentially contributed to neurodegeneration.  This was determined using patient derived induced pluripotent stem cells differentiated into motor neurons and compared to control lines.  The iPSC-MN with the variation showed decreased dendritic complexity, aberrant spontaneous firing and decreased survival.  

The authors used Axion's MEA system to record the neuronal activity, in particular the spontaneous electrical firing of both control and ATP7A iPSC-MNs.  At early timepoints the ATP7A iPSC-MNs exhibited hyperexcitability which transitioned to hypoexcitability at later time points.