Modelling the pathogenesis of X-linked distal hereditary motor neuropathy using patient-derived iPSCs

Dis Model Mech. 2020 Jan 13;13(2):dmm041541. doi: 10.1242/dmm.041541.

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.

Keywords: ATP7A; Copper; Induced pluripotent stem cell; Motor neurons; dHMN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Differentiation
  • Copper / metabolism
  • Copper-Transporting ATPases / genetics
  • Down-Regulation / genetics
  • Energy Metabolism
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Genetic Diseases, X-Linked / pathology*
  • Homeostasis
  • Humans
  • Induced Pluripotent Stem Cells / pathology*
  • Karyotype
  • Mitochondria / metabolism
  • Models, Biological*
  • Motor Neurons / pathology
  • Muscular Atrophy, Spinal / pathology*
  • Mutation / genetics
  • Phenotype
  • Spinal Cord / pathology

Substances

  • Copper
  • ATP7A protein, human
  • Copper-Transporting ATPases