Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive
neurodegenerative disease characterized by axonal dystrophy, abnormal
iron deposition and cerebellar
atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca(2+)-independent
phospholipase A(2) (
iPLA(2) or
iPLA(2)β). Here we show that genetic ablation of PLA2G6 in mice (
iPLA(2)β(-/-)) leads to the development of cerebellar
atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive
astrogliosis, the activation of microglial cells, and the pronounced up-regulation of the pro-inflammatory
cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, glial cell activation and the elevation in TNF-α and IL-1β expression occurred before apparent cerebellar
atrophy. Our findings indicate that the absence of PLA2G6 causes
neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar
atrophy. Our study suggests that
iPLA(2)β(-/-) mice are a valuable model for cerebellar
atrophy in INAD and that early anti-inflammatory
therapy may help slow the progression of cerebellar
atrophy in this deadly
neurodegenerative disease.