Establishment of an improved mouse model for infantile neuroaxonal dystrophy that shows early disease onset and bears a point mutation in Pla2g6

Haruka Wada, Takuwa Yasuda, Ikuo Miura, Kazuhiko Watabe, Chika Sawa, Hajime Kamijuku, Satoshi Kojo, Masaru Taniguchi, Ichizo Nishino, Shigeharu Wakana, Hisahiro Yoshida, Ken Ichiro Seino

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42 Citations (Scopus)

Abstract

Calcium-independent group VIA phospholipase A2 (iPLA2β), encoded by PLA2G6, has been shown to be involved in various physiological and pathological processes, including immunity, cell death, and cell membrane homeostasis. Mutations in the PLA2G6 gene have been recently identified in patients with infantile neuroaxonal dystrophy (INAD). Subsequently, it was reported that similar neurological impairment occurs in gene-targeted mice with a null mutation of iPLA2β, whose disease onset became apparent approximately 1 to 2 years after birth. Here, we report the establishment of an improved mouse model for INAD that bears a point mutation in the ankyrin repeat domain of Pla2g6 generated by N-ethyl-N-nitrosourea mutagenesis. These mutant mice developed severe motor dysfunction, including abnormal gait and poor performance in the hanging grip test, as early as 7 to 8 weeks of age, in a manner following Mendelian law. Neuropathological examination revealed widespread formation of spheroids containing tubulovesicular membranes similar to human INAD. Molecular and biochemical analysis revealed that the mutant mice expressed Pla2g6 mRNA and protein, but the mutated Pla2g6 protein had no glycerophospholipid-catalyzing enzyme activity. Because of the significantly early onset of the disease, this mouse mutant (Pla2g6-inad) could be highly useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration.

Original languageEnglish
Pages (from-to)2257-2263
Number of pages7
JournalAmerican Journal of Pathology
Volume175
Issue number6
DOIs
Publication statusPublished - Jan 1 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Wada, H., Yasuda, T., Miura, I., Watabe, K., Sawa, C., Kamijuku, H., Kojo, S., Taniguchi, M., Nishino, I., Wakana, S., Yoshida, H., & Seino, K. I. (2009). Establishment of an improved mouse model for infantile neuroaxonal dystrophy that shows early disease onset and bears a point mutation in Pla2g6. American Journal of Pathology, 175(6), 2257-2263. https://doi.org/10.2353/ajpath.2009.090343