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In the neurodegenerative disease INAD, infantile neuroaxonal dystrophy, glutamate‐ and ATP‐induced Ca 2+ signaling is disturbed in neurons and astrocytes, with mitochondrial dysfunction
Author(s) -
Reiser Georg,
Strokin Mikhail
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb156
Subject(s) - biology , glutamate receptor , mutation , phospholipase , allele , gene , mutant , microbiology and biotechnology , genetics , biochemistry , receptor , enzyme
About 85% of cases of INAD (infantile neuroaxonal dystrophy, OMIM #256600), an autosom al recessive inherited degenerative disease with early onset can be associated with mutations of the PLA2G6 gene . Ca 2+ ‐independent phospholipase A 2 (VIA iPLA 2 ) is encoded in PLA2G6 . However, connections of these mutations to disease are unclear. For the mainly phospholipid metabolizing VIA iPLA 2 also so‐called non‐canonical functions were discussed and reported. These are regulation of store‐regulated Ca 2+ entry in cells and change in mitochondrial Ca 2+ homeostasis. In this study, we investigate glutamate‐evoked Ca 2+ signals in neurons and astrocytes in co‐culture from three INAD mouse models with Pla2g6 gene mutations. The strain‐1 has a hypomorphic Pla2g6 allele with reduced transcript levels (5% of wild type), the strain‐2 has knocked‐out Pla2g6 , and strain‐3 has a Pla2g6 point mutation with the VIA iPLA 2 inactive. It is shown that homozygous offspring from all strains develop pathology similar to that observed in INAD patients. We demonstrate in our present study a strongly reduced glutamate‐induced Ca 2+ response in mutants in astrocytes compared to control cells. When we elucidate the mechanism we find that reduced Ca 2+ responses are due to about 2‐fold‐reduced Glu‐induced capacitative Ca 2+ entry in astrocytes in all three mouse strains. This effect is based on the lack in VIA iPLA 2 activity since we could mimic the decrease by pharmacologically inhibiting iPLA 2 with the compound S‐BEL enantiomer. On the contrary, in neurons the Pla2g6 mutation completely disrupted the influence of mitochondrial Ca 2+ uptake on the extracellular Glu‐induced Ca 2+ influx . We see it in neurons treated with Ru360, a blocker of mitochondrial Ca 2+ uniporter or treated with rotenone. The dependency of Glu‐induced Ca 2+ influx on mitochondrial Ca 2+ uptake was wiped out in neurons with Pla2g6 mutation, whereas a strong reduction was seen in wild‐type cells. Thus, all INAD models have comparable changes, but they are different for astrocytes and neurons, respectively, in Glu‐induced Ca 2+ signaling. These modifications in Ca 2+ signaling in cells with mutated Pla2g6 are critical for adequate neuron‐astrocyte communication. Thus our data help to understand molecular mechanisms of INAD pathology. Support or Funding Information Deutsche Forschungsgemeinschaft (Re 563‐22‐1)