Differentiation but not ALS mutations in FUS rewires motor neuron metabolism

Nat Commun. 2019 Sep 12;10(1):4147. doi: 10.1038/s41467-019-12099-4.

Abstract

Energy metabolism has been repeatedly linked to amyotrophic lateral sclerosis (ALS). Yet, motor neuron (MN) metabolism remains poorly studied and it is unknown if ALS MNs differ metabolically from healthy MNs. To address this question, we first performed a metabolic characterization of induced pluripotent stem cells (iPSCs) versus iPSC-derived MNs and subsequently compared MNs from ALS patients carrying FUS mutations to their CRISPR/Cas9-corrected counterparts. We discovered that human iPSCs undergo a lactate oxidation-fuelled prooxidative metabolic switch when they differentiate into functional MNs. Simultaneously, they rewire metabolic routes to import pyruvate into the TCA cycle in an energy substrate specific way. By comparing patient-derived MNs and their isogenic controls, we show that ALS-causing mutations in FUS did not affect glycolytic or mitochondrial energy metabolism of human MNs in vitro. These data show that metabolic dysfunction is not the underlying cause of the ALS-related phenotypes previously observed in these MNs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Case-Control Studies
  • Cell Differentiation*
  • Cell Respiration
  • Glucose / metabolism
  • Glycolysis
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Lactic Acid / metabolism
  • Metabolic Flux Analysis
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology*
  • Motor Neurons / ultrastructure
  • Mutation / genetics*
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / metabolism

Substances

  • RNA-Binding Protein FUS
  • Lactic Acid
  • Glucose