PMID- 27434582
OWN - NLM
STAT- MEDLINE
DCOM- 20170621
LR  - 20220331
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 14
IP  - 7
DP  - 2016 Jul
TI  - Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram 
      Syndrome.
PG  - e1002511
LID - 10.1371/journal.pbio.1002511 [doi]
LID - e1002511
AB  - Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple 
      neurological and psychiatric abnormalities similar to those observed in 
      pathologies showing alterations in mitochondrial dynamics. The aim of this study 
      was to examine the hypothesis that WFS1 deficiency affects neuronal function via 
      mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons 
      leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial 
      fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying 
      neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, 
      leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed 
      cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. 
      Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial 
      dynamics, and delayed neuronal development are causatively related events because 
      interventions at all these levels improved the downstream processes. Our data 
      shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and 
      point out potential therapeutic targets. This work may have broader implications 
      for understanding the role of mitochondrial dynamics in neuropsychiatric 
      diseases.
FAU - Cagalinec, Michal
AU  - Cagalinec M
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
AD  - Department of Muscle Cell Research, Institute of Molecular Physiology and 
      Genetics, Slovak Academy of Sciences, Bratislava, Slovakia.
FAU - Liiv, Mailis
AU  - Liiv M
AUID- ORCID: 0000-0001-6203-4810
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Hodurova, Zuzana
AU  - Hodurova Z
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Hickey, Miriam Ann
AU  - Hickey MA
AUID- ORCID: 0000-0002-3363-8583
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Vaarmann, Annika
AU  - Vaarmann A
AUID- ORCID: 0000-0003-0296-8325
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Mandel, Merle
AU  - Mandel M
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Zeb, Akbar
AU  - Zeb A
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Choubey, Vinay
AU  - Choubey V
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Kuum, Malle
AU  - Kuum M
AUID- ORCID: 0000-0002-4681-1859
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Safiulina, Dzhamilja
AU  - Safiulina D
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Vasar, Eero
AU  - Vasar E
AD  - Department of Physiology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
FAU - Veksler, Vladimir
AU  - Veksler V
AD  - INSERM U-1180, Chatenay-Malabry, France.
AD  - University Paris-Saclay, Chatenay-Malabry, France.
FAU - Kaasik, Allen
AU  - Kaasik A
AD  - Department of Pharmacology, Institute of Biomedicine and Translational Medicine, 
      University of Tartu, Tartu, Estonia.
LA  - eng
PT  - Journal Article
DEP - 20160719
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (Inositol 1,4,5-Trisphosphate Receptors)
RN  - 0 (Membrane Proteins)
RN  - 0 (wolframin protein)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Brain/cytology/metabolism
MH  - Calcium/metabolism
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum Stress/genetics
MH  - Fluorescence Resonance Energy Transfer
MH  - Homeostasis
MH  - Humans
MH  - Inositol 1,4,5-Trisphosphate Receptors/metabolism
MH  - Membrane Potential, Mitochondrial/genetics
MH  - Membrane Proteins/genetics/metabolism
MH  - Mice, Knockout
MH  - Microscopy, Confocal
MH  - Mitochondria/genetics/*metabolism
MH  - *Mitochondrial Dynamics
MH  - Mitophagy/genetics
MH  - *Neurogenesis
MH  - Neurons/cytology/*metabolism
MH  - PC12 Cells
MH  - RNA Interference
MH  - Rats
MH  - Rats, Wistar
MH  - Time-Lapse Imaging/methods
MH  - Wolfram Syndrome/genetics/metabolism
PMC - PMC4951053
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/07/21 06:00
MHDA- 2017/06/22 06:00
PMCR- 2016/07/19
CRDT- 2016/07/20 06:00
PHST- 2016/01/22 00:00 [received]
PHST- 2016/06/13 00:00 [accepted]
PHST- 2016/07/20 06:00 [entrez]
PHST- 2016/07/21 06:00 [pubmed]
PHST- 2017/06/22 06:00 [medline]
PHST- 2016/07/19 00:00 [pmc-release]
AID - PBIOLOGY-D-16-00153 [pii]
AID - 10.1371/journal.pbio.1002511 [doi]
PST - epublish
SO  - PLoS Biol. 2016 Jul 19;14(7):e1002511. doi: 10.1371/journal.pbio.1002511. 
      eCollection 2016 Jul.