Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs
The Company of Biologists -- Disease Models & Mechanisms
DOI 10.1242/dmm.041541
Keyword(s)
  1. ATP7A
  2. Copper
  3. Induced pluripotent stem cell
  4. Motor neurons
  5. dHMN
Abstract(s)

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.