PMID- 22442204
OWN - NLM
STAT- MEDLINE
DCOM- 20121009
LR  - 20211021
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 21
IP  - 12
DP  - 2012 Jun 15
TI  - Severe disturbance in the Ca2+ signaling in astrocytes from mouse models of human 
      infantile neuroaxonal dystrophy with mutated Pla2g6.
PG  - 2807-14
LID - 10.1093/hmg/dds108 [doi]
AB  - Infantile neuroaxonal dystrophy (INAD; OMIM #no. 256600) is an inherited 
      degenerative nervous system disorder characterized by nerve abnormalities in 
      brain, spinal cord and peripheral nerves. About 85% of INAD patients carry 
      mutations in the PLA2G6 gene that encodes for a Ca(2+)-independent phospholipase 
      A(2) (VIA iPLA(2)), but how these mutations lead to disease is unknown. Besides 
      regulating phospholipid homeostasis, VIA iPLA(2) is emerging with additional 
      non-canonical functions, such as modulating store-regulated Ca(2+) entry into 
      cells, and mitochondrial functions. In turn, defective Ca(2+) regulation could 
      contribute to the development of INAD. Here, we studied possible changes in 
      ATP-induced Ca(2+) signaling in astrocytes derived from two mutant strains of 
      mice. The first strain carries a hypomorphic allele of the Pla2g6 that reduces 
      transcript levels to 5-10% of that observed in wild-type mice. The second strain 
      carries a point mutation in Pla2g6 that results in inactive VIA iPLA(2) protein 
      with postulated gain in toxicity. Homozygous mice from both strains develop 
      pathology analogous to that observed in INAD patients. The nucleotide ATP is the 
      most important transmitter inducing Ca(2+) signals in astroglial networks. We 
      demonstrate here a severe disturbance in Ca(2+) responses to ATP in astrocytes 
      derived from both mutant mouse strains. The duration of the Ca(2+) responses in 
      mutant astrocytes was significantly reduced when compared with values observed in 
      control cells. We also show that the reduced Ca(2+) responses are probably due to 
      a reduction in capacitative Ca(2+) entry (2.3-fold). Results suggest that altered 
      Ca(2+) signaling could be a central mechanism in the development of INAD 
      pathology.
FAU - Strokin, Mikhail
AU  - Strokin M
AD  - Institut fur Neurobiochemie, Medizinische Fakultat, Otto-von-Guericke-Universitat 
      Magdeburg, Magdeburg, Germany.
FAU - Seburn, Kevin L
AU  - Seburn KL
FAU - Cox, Gregory A
AU  - Cox GA
FAU - Martens, Kimberly A
AU  - Martens KA
FAU - Reiser, Georg
AU  - Reiser G
LA  - eng
GR  - R01 NS054154/NS/NINDS NIH HHS/United States
GR  - NS054154/NS/NINDS NIH HHS/United States
GR  - AR054170/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120322
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - EC 3.1.1.4 (PLA2G6 protein, human)
RN  - EC 3.1.1.4 (Pla2g6 protein, mouse)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adenosine Triphosphate/pharmacology
MH  - Animals
MH  - Astrocytes/drug effects/*metabolism
MH  - Calcium/*metabolism
MH  - Calcium Signaling/drug effects
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Gene Expression
MH  - Genotype
MH  - Group VI Phospholipases A2/*genetics/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C3H
MH  - Mice, Knockout
MH  - *Mutation
MH  - Neuroaxonal Dystrophies/*genetics/metabolism/pathology
MH  - Reverse Transcriptase Polymerase Chain Reaction
PMC - PMC3363330
EDAT- 2012/03/24 06:00
MHDA- 2012/10/10 06:00
PMCR- 2013/06/15
CRDT- 2012/03/24 06:00
PHST- 2012/03/24 06:00 [entrez]
PHST- 2012/03/24 06:00 [pubmed]
PHST- 2012/10/10 06:00 [medline]
PHST- 2013/06/15 00:00 [pmc-release]
AID - dds108 [pii]
AID - 10.1093/hmg/dds108 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2012 Jun 15;21(12):2807-14. doi: 10.1093/hmg/dds108. Epub 2012 Mar 
      22.