Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs
Gonzalo Pérez‐Siles, Anthony N. Cutrupi, Melina Ellis, Jakob Kuriakose, Sharon La Fontaine, Di Mao, Motonari Uesugi, Reinaldo Issao Takata, Carlos E. Speck‐Martins, Garth A. Nicholson, Marina Kennerson
Abstract
ABSTRACT ATP7A encodes a copper-transporting P-type ATPase and is one of 23 genes in which mutations produce distal hereditary motor neuropathy (dHMN), a group of diseases characterized by length-dependent axonal degeneration of motor neurons. We have generated induced pluripotent stem cell (iPSC)-derived motor neurons from a patient with the p.T994I ATP7A gene mutation as an in vitro model for X-linked dHMN (dHMNX). Patient motor neurons show a marked reduction of ATP7A protein levels in the soma when compared to control motor neurons and failed to upregulate expression of ATP7A under copper-loading conditions. These results recapitulate previous findings obtained in dHMNX patient fibroblasts and in primary cells from a rodent model of dHMNX, indicating that patient iPSC-derived motor neurons will be an important resource for studying the role of copper in the pathogenic processes that lead to axonal degeneration in dHMNX.