Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotempora
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RESEARCH
Open Access
Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotemporal dementia Blanca I. Aldana1†, Yu Zhang2,3†, Pia Jensen4, Abinaya Chandrasekaran2, Sofie K. Christensen1, Troels T. Nielsen5, Jørgen E. Nielsen5, Poul Hyttel2, Martin R. Larsen4, Helle S. Waagepetersen1 and Kristine K. Freude2*
Abstract Frontotemporal dementia (FTD) is amongst the most prevalent early onset dementias and even though it is clinically, pathologically and genetically heterogeneous, a crucial involvement of metabolic perturbations in FTD pathology is being recognized. However, changes in metabolism at the cellular level, implicated in FTD and in neurodegeneration in general, are still poorly understood. Here we generate induced human pluripotent stem cells (hiPSCs) from patients carrying mutations in CHMP2B (FTD3) and isogenic controls generated via CRISPR/Cas9 gene editing with subsequent neuronal and glial differentiation and characterization. FTD3 neurons show a dysregulation of glutamate-glutamine related metabolic pathways mapped by 13C-labelling coupled to mass spectrometry. FTD3 astrocytes show increased uptake of glutamate whilst glutamate metabolism is largely maintained. Using quantitative proteomics and live-cell metabolic analyses, we elucidate molecular determinants and functional alterations of neuronal and glial energy metabolism in FTD3. Importantly, correction of the mutations rescues such pathological phenotypes. Notably, these findings implicate dysregulation of key enzymes crucial for glutamateglutamine homeostasis in FTD3 pathogenesis which may underlie vulnerability to neurodegeneration. Keywords: FTD3, CHMP2B, iPSC-derived neuron, Glucose metabolism, Glutamate, Glutamine, GC-MS, GDH, PAG, GS
Introduction Frontotemporal dementia (FTD) is a leading type of earlyonset dementia and involves progressive brain atrophy largely affecting the frontal and temporal lobes of the brain [1, 2]. While FTD has conventionally been regarded as a syndrome characterized by behavioural and cognitive perturbations, a critical involvement of cerebral metabolic
* Correspondence: [email protected] † Blanca I. Aldana and Yu Zhang contributed equally to this work. 2 Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegårdsvej 7, 1870 Frederiksberg C, Denmark Full list of author information is available at the end of the article
alterations in FTD pathology is now being increasingly recognized [3–5]. Normal brain function requires a large and continuous supply of oxygen and glucose for energy production used mainly to satisfy the high demand of electrical activity and synaptic functions in neurons [6]. Moreover, strict regulation of glutamate and glutamine metabolism is vital both for energy homeostasis and for excitatory neurotransmission [7]. Several neurodegenerative disorders are associated with critical metabolic impairments including diminished glucose uptake and utilization, as well as
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