Neuroaxonal Dystrophy Caused by Group VIA Phospholipase A2Deficiency in Mice: A Model of Human Neurodegenerative Disease

Abstract

Calcium-independent group VIA phospholipase A 2(iPLA 2 β) is considered to play a role in signal transduction and maintenance of homeostasis or remodeling of membrane phospholipids. A role of iPLA 2 β has been suggested in various physiological and pathological processes, including immunity, chemotaxis, and cell death, but the details remain unclear. Accordingly, we investigated mice with targeted disruption of the iPLA 2β gene.iPLA 2β−/−mice developed normally and grew to maturity, but all showed evidence of severe motor dysfunction, including a hindlimb clasping reflex during tail suspension, abnormal gait, and poor performance in the hanging wire grip test. Neuropathological examination of the nervous system revealed widespread degeneration of axons and/or synapses, accompanied by the presence of numerous spheroids (swollen axons) and vacuoles. These findings provide evidence that impairment of iPLA 2β causes neuroaxonal degeneration, and indicate that the iPLA 2β−/−mouse is an appropriate animal model of human neurodegenerative diseases associated with mutations of the iPLA 2β gene, such as infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation.