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.
Highlights
Energy metabolism has been repeatedly linked to amyotrophic lateral sclerosis (ALS)
We show that induced pluripotent stem cells (iPSCs), as they differentiate into functional motor neuron (MN), shift towards a more oxidative phenotype as they reduce glucose uptake and glycolytic flux, but elevate tricarboxylic acid (TCA) cycle activity and respiratory potential
80% of cells stained positive for the pan-neuronal markers Tuj[1] and synapsin[1] and for the MN-specific markers ChAT, Isl[1] and SMI32 without significant differences between any of the lines (Fig. 1c)
Summary
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. 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. As a consequence, more than 80,000 patients who are alive at present will succumb to the disease[3]. We and others found that ALS-causing FUS mutations affect the two most energy demanding biological processes in MNs, neuronal firing and axonal transport, using humaninduced pluripotent stem cell (iPSC)-derived MNs15–18.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
