Mouse Models of Neuroaxonal Dystrophy Caused by PLA2G6 Gene Mutations

Mutations in PLA2G6 cause neuroaxonal dystrophy (NAD), a progressive neurodegenerative disorder affecting movement, speech, and cognition. The hallmark pathologic feature of NAD is neuroaxonal spheroids, a term for the abnormal accumulation of tubulovesicular membrane material in distal neuronal processes. PLA2G6 encodes a phospholipase enzyme that hydrolyzes phospholipids and lysophospholipids to produce free fatty acids. Four independent mouse models of NAD have been reported, each arising from a mutation that profoundly alters the expression or function of PLA2G6 protein. All four models exhibit progressive neurologic impairment accompanied by neuroaxonal spheroid formation throughout the nervous system. However, two models display weakness and muscle atrophy indicative of spinal cord motor neuron degeneration beginning at 2-3. months of age, whereas the other two models develop neurologic deficits characterized primarily by impaired coordination at 12. months. Reasons for these phenotypic differences are unclear on the basis of current knowledge of PLA2G6 enzyme function and genotype-phenotype relationships in human NAD. Nevertheless, these models provide opportunities to further investigate disease mechanisms and test therapeutic approaches in NAD.