Neuroaxonal dystrophy caused by group VIA phospholipase A2 deficiency in mice: a model of human neurodegenerative disease.
Calcium-independent group VIA phospholipase A2 (iPLA2beta) is considered to play a role in signal transduction and maintenance of homeostasis or remodeling of membrane phospholipids. A role of iPLA2beta 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 iPLA2beta gene. iPLA2beta-/- 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 iPLA2beta causes neuroaxonal degeneration, and indicate that the iPLA2beta-/- mouse is an appropriate animal model of human neurodegenerative diseases associated with mutations of the iPLA2beta gene, such as infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation.
Shinzawa
Koei
K
Department of Medical Genetics, Laboratory of Molecular Genetics and Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, Osaka 565-0871, Japan.
Sumi
Hisae
H
Ikawa
Masahito
M
Matsuoka
Yosuke
Y
Okabe
Masaru
M
Sakoda
Saburo
S
Tsujimoto
Yoshihide
Y
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D054522:Group VI Phospholipases A2 / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053580:Muscle Strength / Q000502:physiology; D009420:Nervous System / Q000378:metabolism / Q000473:pathology; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019636:Neurodegenerative Diseases; D012333:RNA, Messenger / Q000378:metabolism
D012333:RNA, Messenger; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse