Genetic Ablation of PLA2G6 in Mice Leads to Cerebellar Atrophy Characterized by Purkinje Cell Loss and Glial Cell Activation

Date

2011-10-28

Authors

Zhao, Zhengshan
Wang, Jing
Zhao, Chunying
Bi, Weina
Yue, Zhenyu
Ma, Zhongmin Alex

Journal Title

Journal ISSN

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Publisher

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 A2 (iPLA2 or iPLA2b). Here we show that genetic ablation of PLA2G6 in 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 upregulation 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 antiinflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease.

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Keywords

Research Article, Biology, Model Organisms, Animal Models, Mouse, Neuroscience, Developmental Neuroscience, Molecular Neuroscience, Medicine, Clinical Genetics, Autosomal Recessive, Clinical Immunology, Immune System, Cytokines, Diagnostic Medicine, Pathology, Anatomical Pathology, Neuropathology, Neurology, Cerebellar Disorders, Neurodegenerative Diseases, Pediatrics, Developmental and Pediatric Neurology

Citation

PLoS One. 2011 Oct 28; 6(10):e26991