Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration

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...

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Bibliographic Details
Published in:Redox biology 2017-08, Vol.12, p.410-422
Main Authors: Esteras, Noemí, Rohrer, Jonathan D, Hardy, John, Wray, Selina, Abramov, Andrey Y
Format: Article
Language:English
Subjects:
Cell Line
Cell Polarity
Frontotemporal Dementia - genetics
Frontotemporal Dementia - metabolism
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Membrane Potential, Mitochondrial
Mitochondria - metabolism
Mitochondria - physiology
Mutation
NAD - metabolism
Neurons - cytology
Neurons - metabolism
Oxidative Phosphorylation
Oxidative Stress
Reactive Oxygen Species - metabolism
Research Paper
tau Proteins - genetics
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Summary: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.
ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2017.03.008