genetic ablation of pla2g6 in mice leads to cerebellar atrophy characterized by purkinje cell loss and glial cell activation小鼠基因消融pla2g6导致小脑萎缩的特征是浦肯野细胞和神经胶质细胞活化损失.pdfVIP

Genetic Ablation of PLA2G6 in Mice Leads to Cerebellar Atrophy Characterized by Purkinje Cell Loss and Glial Cell Activation 1 2 1 1 2 1 Zhengshan Zhao , Jing Wang , Chunying Zhao , Weina Bi , Zhenyu Yue , Zhongmin Alex Ma * 1 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, 2 Department of Neurology, Mount Sinai School of Medicine, New York, New York, United States of America 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 Ca2+-independent phospholipase A (iPLA or iPLA b). Here we show that genetic ablation of PLA2G6 in 2 2 2 mice (iPLA2b-/-) 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-a (TNF-a) and interleukin-1b (IL-1b). Moreover, glial cell activation and the elevation in TNF-a and IL-1b 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 iPLA2b-/- mice are a valuable model for cerebellar atrophy in INAD and that early anti- inflammatory therapy may help slow