PMID- 28279750
OWN - NLM
STAT- MEDLINE
DCOM- 20180413
LR  - 20180413
IS  - 1872-9754 (Electronic)
IS  - 0197-0186 (Linking)
VI  - 108
DP  - 2017 Sep
TI  - Neurons and astrocytes in an infantile neuroaxonal dystrophy (INAD) mouse model 
      show characteristic alterations in glutamate-induced Ca(2+) signaling.
PG  - 121-132
LID - S0197-0186(16)30503-4 [pii]
LID - 10.1016/j.neuint.2017.03.004 [doi]
AB  - INAD (infantile neuroaxonal dystrophy, OMIM#256600), an autosomal recessive 
      inherited degenerative disease, is associated with PLA2G6 mutations. PLA2G6 
      encodes Ca(2+)-independent phospholipase A(2) (VIA iPLA(2)). However, it is 
      unclear how the PLA2G6-mutations lead to disease. Non-canonical functions, which 
      were suggested for VIA iPLA(2), such as regulation of cellular and mitochondrial 
      Ca(2+) are promising candidates. Therefore, we investigate glutamate (Glu)-evoked 
      Ca(2+) signals in neurons and astrocytes in co-culture obtained from three INAD 
      mouse model strains with Pla2g6 mutations, (i) hypomorphic Pla2g6 allele with 
      reduced transcript levels, (ii) knocked-out Pla2g6, and (iii) (G373R)-point 
      mutation with inactive VIA iPLA(2) enzyme. Homozygous offspring from these 
      strains develop pathology similar to that observed in INAD patients. We found 
      that in mouse neurons the Pla2g6 mutation disrupted the dependency of Glu-induced 
      extracellular Ca(2+) influx on mitochondrial Ca(2+) uptake. Thus, in neurons with 
      Pla2g6 mutation we did not detect the characteristic reduction in Glu-induced 
      Ca(2+) influx upon treatment with Ru360, a blocker of mitochondrial Ca(2+) 
      uniporter, or with rotenone. In contrast to neurons, in astrocytes, both with 
      Pla2g6 mutation or wild-type cells, the treatment with Ru360 or rotenone reduced 
      the rate of Glu-induced Ca(2+) influx  approximately 2-fold. This Ca(2+) influx in astrocytes 
      represents capacitative Ca(2+) entry. In astrocytes with Pla2g6 mutation, the 
      Glu-induced Ca(2+) influx was  approximately 2-fold lower than in wild-type controls. We 
      suggest that this is the mechanism for strongly decreased durations of 
      Glu-induced Ca(2+) responses in astrocytes with Pla2g6 mutation. We could mimic 
      the mutation by pharmacological inhibition of iPLA(2) using S-BEL. Thus, lack of 
      VIA iPLA(2) activity caused effects in astrocytes. In summary, three INAD mouse 
      models show comparable changes in Glu-induced Ca(2+) signaling, but specific for 
      neurons or astrocytes. This finding helps to identify pathways altered during 
      INAD and highlights non-canonical VIA iPLA(2) functions, like regulation of 
      cellular Ca(2+) fluxes by mitochondria or capacitative Ca(2+)-entry.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Strokin, Mikhail
AU  - Strokin M
AD  - Institut fur Neurobiochemie (Institut fur Inflammation und Neurodegeneration), 
      Medizinische Fakultat, Otto-von-Guericke-Universitat Magdeburg, Magdeburg, 
      Germany.
FAU - Reiser, Georg
AU  - Reiser G
AD  - Institut fur Neurobiochemie (Institut fur Inflammation und Neurodegeneration), 
      Medizinische Fakultat, Otto-von-Guericke-Universitat Magdeburg, Magdeburg, 
      Germany. Electronic address: georg.reiser@med.ovgu.de.
LA  - eng
PT  - Journal Article
DEP - 20170306
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - EC 3.1.1.4 (Pla2g6 protein, mouse)
SB  - IM
MH  - Animals
MH  - Astrocytes/drug effects/*metabolism
MH  - Calcium Signaling/drug effects/*physiology
MH  - Coculture Techniques
MH  - *Disease Models, Animal
MH  - Female
MH  - Glutamic Acid/*toxicity
MH  - Group VI Phospholipases A2/genetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neuroaxonal Dystrophies/chemically induced/genetics/*metabolism
MH  - Neurons/drug effects/*metabolism
OTO - NOTNLM
OT  - Astrocyte
OT  - Ca(2+) signaling
OT  - Glutamate
OT  - Infantile neuroaxonal dystrophy (INAD)
OT  - Mouse models of INAD
OT  - Neuron
OT  - Phospholipase A(2)
EDAT- 2017/03/11 06:00
MHDA- 2018/04/14 06:00
CRDT- 2017/03/11 06:00
PHST- 2016/12/18 00:00 [received]
PHST- 2017/03/03 00:00 [revised]
PHST- 2017/03/03 00:00 [accepted]
PHST- 2017/03/11 06:00 [pubmed]
PHST- 2018/04/14 06:00 [medline]
PHST- 2017/03/11 06:00 [entrez]
AID - S0197-0186(16)30503-4 [pii]
AID - 10.1016/j.neuint.2017.03.004 [doi]
PST - ppublish
SO  - Neurochem Int. 2017 Sep;108:121-132. doi: 10.1016/j.neuint.2017.03.004. Epub 2017 
      Mar 6.