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.
To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA(2)β knock-out (KO) mice, a model of INAD.
Because of the significantly early onset of the disease, this mouse mutant (Pla2g6-inad) could be highly useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration.
These results indicate that loss of iPLA(2)beta causes age-dependent impairment of axonal membrane homeostasis and protein degradation pathways, leading to age-dependent neurological impairment. iPLA(2)beta-KO mice will be useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration with brain iron accumulation.
These findings provide evidence that impairment of iPLA2beta causes neuroaxonal degeneration, and indicate that the iPLA2beta-/- mouse is an appropriate animal model of human neurodegenerative diseases associated with mutations of the iPLA2beta gene, such as infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation.