Severe disturbance in the Ca²⁺ signaling in astrocytes from mouse models of human infantile neuroaxonal dystrophy with mutated Pla2g6

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.