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

Abstract

Calcium-independent group VIA phospholipase A₂(iPLA₂β) is considered to play a role in signal transduction and maintenance of homeostasis or remodeling of membrane phospholipids. A role of iPLA₂β 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 theiPLA₂β gene.iPLA₂β^−/−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 ofiPLA₂β causes neuroaxonal degeneration, and indicate that theiPLA₂β^−/−mouse is an appropriate animal model of human neurodegenerative diseases associated with mutations of theiPLA₂β gene, such as infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation.