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The Journal of Neuroscience, February 27, 2008, 28(9):2212-2220; doi:10.1523/JNEUROSCI.4354-07.2008

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Neurobiology of Disease
Neuroaxonal Dystrophy Caused by Group VIA Phospholipase A₂ Deficiency in Mice: A Model of Human Neurodegenerative Disease

Koei Shinzawa,¹ Hisae Sumi,² Masahito Ikawa,³ Yosuke Matsuoka,¹ Masaru Okabe,³ Saburo Sakoda,² and Yoshihide Tsujimoto¹

¹Department of Medical Genetics, Laboratory of Molecular Genetics and Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, and ²Department of Neurology, Osaka University Medical School, Osaka 565-0871, Japan, and ³Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

Correspondence should be addressed to Yoshihide Tsujimoto, Laboratory of Molecular Genetics, Osaka University Medical School, Room B8, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Email: tsujimot{at}gene.med.osaka-u.ac.jp

Calcium-independent group VIA phospholipase A₂ (iPLA₂β) is considered to play a role in signal transduction and maintenance of homeostasis or remodeling of membrane phospholipids. A role of iPLA₂β has been suggested in various physiological and pathological processes, including immunity, chemotaxis, and cell death, but the details remain unclear. Accordingly, we investigated mice with targeted disruption of the iPLA₂β gene. iPLA₂β^–/– mice developed normally and grew to maturity, but all showed evidence of severe motor dysfunction, including a hindlimb clasping reflex during tail suspension, abnormal gait, and poor performance in the hanging wire grip test. Neuropathological examination of the nervous system revealed widespread degeneration of axons and/or synapses, accompanied by the presence of numerous spheroids (swollen axons) and vacuoles. These findings provide evidence that impairment of iPLA₂β causes neuroaxonal degeneration, and indicate that the iPLA₂β^–/– mouse is an appropriate animal model of human neurodegenerative diseases associated with mutations of the iPLA₂β gene, such as infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation.

Key words: phospholipase; neurodegeneration; neuroaxonal dystrophy; knock-out mouse; iPLA₂; spheroid

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Received Nov. 22, 2006; revised Jan. 15, 2008; accepted Jan. 17, 2008.

Correspondence should be addressed to Yoshihide Tsujimoto, Laboratory of Molecular Genetics, Osaka University Medical School, Room B8, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Email: tsujimot{at}gene.med.osaka-u.ac.jp

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