Differentiation but not ALS mutations in FUS rewires motor neuron metabolism

Tijs Vandoorne, Koen Veys, Wenting Guo, Adria Sicart, Katlijn Vints, Ann Swijsen, Matthieu Moisse, Guy Eelen, Natalia V. Gounko, Laura Fumagalli, Raheem Fazal, Christine Germeys, Annelies Quaegebeur, Sarah-Maria Fendt, Peter Carmeliet, Catherine Verfaillie, Philip Van Damme, Bart Ghesquière, Katrien De Bock and Ludo Van Den Bosch ()
Additional contact information
Tijs Vandoorne: KU Leuven – University of Leuven
Koen Veys: Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven – University of Leuven
Wenting Guo: KU Leuven – University of Leuven
Adria Sicart: KU Leuven – University of Leuven
Katlijn Vints: Electron Microscopy Platform and VIB Bioimaging core facility
Ann Swijsen: KU Leuven – University of Leuven
Matthieu Moisse: KU Leuven – University of Leuven
Guy Eelen: Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven – University of Leuven
Natalia V. Gounko: Electron Microscopy Platform and VIB Bioimaging core facility
Laura Fumagalli: KU Leuven – University of Leuven
Raheem Fazal: KU Leuven – University of Leuven
Christine Germeys: KU Leuven – University of Leuven
Annelies Quaegebeur: University College London Hospitals NHS Foundation Trust
Sarah-Maria Fendt: Laboratory of Cellular Metabolism and Metabolic Regulation
Peter Carmeliet: Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven – University of Leuven
Catherine Verfaillie: KU Leuven – University of Leuven
Philip Van Damme: KU Leuven – University of Leuven
Bart Ghesquière: KU Leuven – University of Leuven
Katrien De Bock: Laboratory of Exercise and Health
Ludo Van Den Bosch: KU Leuven – University of Leuven

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12099-4

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