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 Ca2+-independent phospholipase A2 (VIA iPLA2), but how these mutations lead to disease is unknown. Besides regulating phospholipid homeostasis, VIA iPLA2 is emerging with additional non-canonical functions, such as modulating store-regulated Ca2+ entry into cells, and mitochondrial functions. In turn, defective Ca2+ regulation could contribute to the development of INAD. Here, we studied possible changes in ATP-induced Ca2+ 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 iPLA2 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 Ca2+ signals in astroglial networks. We demonstrate here a severe disturbance in Ca2+ responses to ATP in astrocytes derived from both mutant mouse strains. The duration of the Ca2+ responses in mutant astrocytes was significantly reduced when compared with values observed in control cells. We also show that the reduced Ca2+ responses are probably due to a reduction in capacitative Ca2+ entry (2.3-fold). Results suggest that altered Ca2+ signaling could be a central mechanism in the development of INAD pathology.
Mikhail Strokin; Kevin L. Seburn; Gregory A. Cox; Kimberly A. Martens; Georg Reiser
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