Energy Metabolism and Mitochondrial Superoxide Anion Production in Pre-symptomatic Striatal Neurons Derived from Human-Induced Pluripotent Stem Cells Expressing Mutant Huntingtin

CRISPR/Cas9 Mediated Gene Modification Ameliorates Abnormal Phenotypes in SCA3/MJD Disease Patient Derived Induced Pluripotent Stem Cells

“…At this stage, there were no signi cant differences in TUJ1/GFAP and MAP2/GABA positive cells among the Ctrl-NCs, SCA3/MJD-NCs and corrected SCA3/MJD-NCs (C3, C12) groups (Fig. 5a-f).Therefore, our protocols of iPSCs differentiated into neurons and astrocytes was consistent with previous studies, in which the transformation of iPSCs led to a mixture of cultured neurons and astrocytes [41,42]. Further analysis revealed that SYP1/PSD95, which is the pre-and post-synaptic marker of synaptic development, expressed similarly in four groups at days 40~60 differentiation as previously reported (Fig.…”

Mitochondrial and Redox Modifications in Huntington Disease Induced Pluripotent Stem Cells Rescued by CRISPR/Cas9 CAGs Targeting

“…Moreover, proteomic analysis in the same 72 CAG HD-iPSC used in this work showed that antioxidant enzymes, such as SOD1 or peroxiredoxin (Prx) were downregulated or up-regulated, respectively, ( Chae et al, 2012 ). While we observed mitochondrial abnormalities, other researchers reported the absence of mitochondrial dysfunction, claiming that bioenergetic deficits and ROS production are not decisive factors in HD pathology in the pre-symptomatic stage despite recognizing the involvement at later stages of the disease ( Hamilton et al, 2020 ). The reason for this discrepancy is not clear but could be attributed to differences in cell culture and/or methodologies.…”

Metabolic Aspects of Adenosine Functions in the Brain

“…The authors suggested that mutated HTT could interact with and suppress the activity of the extracellular enzymes involved in nucleotide catabolism thereby contributing to HD pathology (Toczek et al, 2018). More recently, human astrocytes and striatal neurons have been obtained from pluripotent stem cells (iPSCs) derived from unaffected individuals and HD patients with HTT gene containing increased number of CAG repeats and used to study the effect of mutant HTT on bioenergetics (HD iPSC Consortium, 2020;Hamilton et al, 2020). While the neurons and astrocytes obtained from iPSCs of control individuals and HD patients had similar levels of ADP and ATP and comparable respiratory and glycolytic activities (Hamilton et al, 2020), the neurons with longer CAG tails, reflecting a more advanced stage of the disease (HD iPSC Consortium, 2020), showed decreased ATP levels and reduced expression of glycolytic enzymes compared to controls.…”

“…More recently, human astrocytes and striatal neurons have been obtained from pluripotent stem cells (iPSCs) derived from unaffected individuals and HD patients with HTT gene containing increased number of CAG repeats and used to study the effect of mutant HTT on bioenergetics (HD iPSC Consortium, 2020;Hamilton et al, 2020). While the neurons and astrocytes obtained from iPSCs of control individuals and HD patients had similar levels of ADP and ATP and comparable respiratory and glycolytic activities (Hamilton et al, 2020), the neurons with longer CAG tails, reflecting a more advanced stage of the disease (HD iPSC Consortium, 2020), showed decreased ATP levels and reduced expression of glycolytic enzymes compared to controls. In addition, ATP levels in these HD neurons could be rescued by addition of pyruvate suggesting that the glycolytic deficits play a role in the metabolic disturbance of HD neurons (HD iPSC Consortium, 2020).…”