PMID- 28319892
OWN - NLM
STAT- MEDLINE
DCOM- 20180320
LR  - 20220129
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 12
DP  - 2017 Aug
TI  - Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 
      with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration.
PG  - 410-422
LID - S2213-2317(17)30104-0 [pii]
LID - 10.1016/j.redox.2017.03.008 [doi]
AB  - 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.
CI  - Copyright (c) 2017 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Esteras, Noemi
AU  - Esteras N
AD  - Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, 
      WC1N 3BG London, UK. Electronic address: n.gallego@ucl.ac.uk.
FAU - Rohrer, Jonathan D
AU  - Rohrer JD
AD  - Dementia Research Centre, UCL Institute of Neurology, London, UK.
FAU - Hardy, John
AU  - Hardy J
AD  - Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, 
      WC1N 3BG London, UK.
FAU - Wray, Selina
AU  - Wray S
AD  - Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, 
      WC1N 3BG London, UK.
FAU - Abramov, Andrey Y
AU  - Abramov AY
AD  - Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, 
      WC1N 3BG London, UK. Electronic address: a.abramov@ucl.ac.uk.
LA  - eng
GR  - MR/J009482/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/M008525/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/M023664/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170310
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (MAPT protein, human)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (tau Proteins)
RN  - 0U46U6E8UK (NAD)
SB  - IM
MH  - Cell Line
MH  - Cell Polarity
MH  - Frontotemporal Dementia/*genetics/metabolism
MH  - Humans
MH  - Induced Pluripotent Stem Cells/cytology/metabolism
MH  - Membrane Potential, Mitochondrial
MH  - Mitochondria/metabolism/*physiology
MH  - Mutation
MH  - NAD/metabolism
MH  - Neurons/*cytology/metabolism
MH  - Oxidative Phosphorylation
MH  - Oxidative Stress
MH  - Reactive Oxygen Species/metabolism
MH  - tau Proteins/*genetics
PMC - PMC5357682
OTO - NOTNLM
OT  - Glycolysis
OT  - Hyperpolarization
OT  - Mitochondria
OT  - Oxidative stress
OT  - Tau
OT  - iPSC-derived neurons
EDAT- 2017/03/21 06:00
MHDA- 2018/03/21 06:00
PMCR- 2017/03/10
CRDT- 2017/03/21 06:00
PHST- 2017/02/09 00:00 [received]
PHST- 2017/03/03 00:00 [revised]
PHST- 2017/03/07 00:00 [accepted]
PHST- 2017/03/21 06:00 [pubmed]
PHST- 2018/03/21 06:00 [medline]
PHST- 2017/03/21 06:00 [entrez]
PHST- 2017/03/10 00:00 [pmc-release]
AID - S2213-2317(17)30104-0 [pii]
AID - 10.1016/j.redox.2017.03.008 [doi]
PST - ppublish
SO  - Redox Biol. 2017 Aug;12:410-422. doi: 10.1016/j.redox.2017.03.008. Epub 2017 Mar 
      10.