Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotemporal dementia
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Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotemporal dementia. / Aldana, Blanca I.; Zhang, Yu; Jensen, Pia; Chandrasekaran, Abinaya; Christensen, Sofie K.; Nielsen, Troels T.; Nielsen, Jørgen E.; Hyttel, Poul; Larsen, Martin R.; Waagepetersen, Helle S.; Freude, Kristine K.
In: Molecular Brain, Vol. 13, No. 1, 125, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Glutamate-glutamine homeostasis is perturbed in neurons and astrocytes derived from patient iPSC models of frontotemporal dementia
AU - Aldana, Blanca I.
AU - Zhang, Yu
AU - Jensen, Pia
AU - Chandrasekaran, Abinaya
AU - Christensen, Sofie K.
AU - Nielsen, Troels T.
AU - Nielsen, Jørgen E.
AU - Hyttel, Poul
AU - Larsen, Martin R.
AU - Waagepetersen, Helle S.
AU - Freude, Kristine K.
PY - 2020
Y1 - 2020
N2 - 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 glutamate-glutamine homeostasis in FTD3 pathogenesis which may underlie vulnerability to neurodegeneration.
AB - 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 glutamate-glutamine homeostasis in FTD3 pathogenesis which may underlie vulnerability to neurodegeneration.
U2 - 10.1186/s13041-020-00658-6
DO - 10.1186/s13041-020-00658-6
M3 - Journal article
C2 - 32928252
VL - 13
JO - Molecular Brain
JF - Molecular Brain
SN - 1756-6606
IS - 1
M1 - 125
ER -
ID: 248500660