title: Genetic ablation of PLA2G6 in mice leads to cerebellar atrophy characterized by Purkinje cell loss and glial cell activation.
abstract: 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.
authors: Division of Experimental Diabetes and Aging, Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, New York, New York, United States of America.
authors: Zhengshan
authors: Z
authors: Zhao
authors: Jing
authors: J
authors: Wang
authors: Chunying
authors: C
authors: Zhao
authors: Weina
authors: W
authors: Bi
authors: Zhenyu
authors: Z
authors: Yue
authors: Zhongmin Alex
authors: ZA
authors: Ma
mesh_terms: D000818:Animals; D001284:Atrophy / Q000235:genetics*; D002526:Cerebellar Diseases / Q000235:genetics / Q000473:pathology*; D054522:Group VI Phospholipases A2 / Q000172:deficiency* / Q000235:genetics; D053583:Interleukin-1beta; D051379:Mice; D017628:Microglia; D019150:Neuroaxonal Dystrophies; D009457:Neuroglia / Q000276:immunology / Q000473:pathology*; D011689:Purkinje Cells / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse