Abstract
Tau protein inclusions are a frequent hallmark of a variety of neurodegenerative disorders. The 10+16 intronic mutation in MAPT gene, encoding tau, causes frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), by altering the splicing of the gene and inducing an increase in the production of 4R tau isoforms, which are more prone to aggregation. However, the molecular mechanisms linking increased 4R tau to neurodegeneration are not well understood.Here, we have used iPSC-derived neurons from patients of FTDP-17 carrying the 10+16 mutation to study the molecular mechanisms underlying neurodegeneration.We show that mitochondrial function is altered in the neurons of the patients. We found that FTDP-17 neurons present an increased mitochondrial membrane potential, which is partially maintained by the F1Fo ATPase working in reverse mode. The 10+16 MAPT mutation is also associated with lower mitochondrial NADH levels, partially supressed complex I-driven respiration, and lower ATP production by oxidative phosphorylation, with cells relying on glycolysis to maintain ATP levels. Increased mitochondrial membrane potential in FTDP-17 neurons leads to overproduction of the ROS in mitochondria, which in turn causes oxidative stress and cell death. Mitochondrial ROS overproduction in these cells is a major trigger for neuronal cell death and can be prevented by mitochondrial antioxidants
Highlights
Tau protein is implicated in the pathogenesis of several clinically diverse neurodegenerative disorders collectively termed the tauopathies
An imbalance in the 3R/4 microtubule-binding repeats (4R) ratio is observed in the sporadic tauopathies progressive supranuclear palsy (PSP) and Abbreviations: 2-NBDG, 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose; AD, Alzheimer's disease; corticobasal degeneration (CBD), Corticobasal Degeneration; CSF, Cerebrospinal Fluid; DHE, Dihydroethidium; ETC, Electron Transport Chain; FCCP, Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; frontotemporal dementia (FTD), Frontotemporal dementia; FTDP-17, Frontotemporal Dementia with Parkinsonism linked to chromosome 17; human embryonic stem cell line (hESC), Human Embryonic Stem Cells; iodoacetic acid (IAA), Iodoacetic Acid; induced pluripotent stem cells (iPSC), Induced Pluripotent Stem Cells; NaPyr, Sodium Pyruvate; OXPHOS, Oxidative Phosphorylation; pyruvate dehydrogenase (PDH), Pyruvate Dehydrogenase; pyruvate dehydrogenase kinase (PDK), Pyruvate Dehydrogenase Kinase; PSP, Progressive Nuclear Palsy; Reactive oxygen species (ROS), Reactive Oxygen Species; TCA cycle, tricarboxylic acid cycle; TMRM, tetramethylrhodamine methyl ester; VDAC, Voltage Dependent Anion Channel; ΔΨm, Mitochondrial Membrane Potential
We show that the 10+16 MAPT mutation induces an impairment of the mitochondrial function: neurons from the patients present alterations in the bioenergetics, with a reduced NADH mitochondrial pool resulting in decreased respiration, and a reduction of the ATP produced by oxidative phosphorylation which is compensated by an increased production of ATP by glycolysis. 10+16 MAPT mutation is associated with a higher mitochondrial membrane potential that leads to an increase in ROS production, oxidative stress and cell death
Summary
Tau protein is implicated in the pathogenesis of several clinically diverse neurodegenerative disorders collectively termed the tauopathies. An imbalance in the 3R/4R ratio is observed in the sporadic tauopathies PSP and Abbreviations: 2-NBDG, 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose; AD, Alzheimer's disease; CBD, Corticobasal Degeneration; CSF, Cerebrospinal Fluid; DHE, Dihydroethidium; ETC, Electron Transport Chain; FCCP, Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FTD, Frontotemporal dementia; FTDP-17, Frontotemporal Dementia with Parkinsonism linked to chromosome 17; hESC, Human Embryonic Stem Cells; IAA, Iodoacetic Acid; iPSC, Induced Pluripotent Stem Cells; NaPyr, Sodium Pyruvate; OXPHOS, Oxidative Phosphorylation; PDH, Pyruvate Dehydrogenase; PDK, Pyruvate Dehydrogenase Kinase; PSP, Progressive Nuclear Palsy; ROS, Reactive Oxygen Species; TCA cycle, tricarboxylic acid cycle; TMRM, tetramethylrhodamine methyl ester; VDAC, Voltage Dependent Anion Channel; ΔΨm, Mitochondrial Membrane Potential. At extended time-points, iPSC-derived neurons recapitulate the tau expression and splicing patterns observed in human brain development This model represents a promising approach for the study of the molecular mechanisms of tau pathology occurring in FTD. We show that the 10+16 MAPT mutation induces an impairment of the mitochondrial function: neurons from the patients present alterations in the bioenergetics, with a reduced NADH mitochondrial pool resulting in decreased respiration, and a reduction of the ATP produced by oxidative phosphorylation which is compensated by an increased production of ATP by glycolysis. 10+16 MAPT mutation is associated with a higher mitochondrial membrane potential that leads to an increase in ROS production, oxidative stress and cell death
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