Publication: Mouse models of human INAD by Pla2g6 deficiency
Authors
Wada, Haruka ; Kojo, Satoshi ; Seino, Ken-ichiro
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Publisher
F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Infantile neuroaxonal dystrophy (INAD) is a
severe neurodegenerative disease characterized by its
early onset. PLA2G6, which encodes a phospholipase
A2, iPLA2ß, has been identified as a causative gene of
INAD. iPLA2ß has been shown to be involved in various
physiological and pathological processes, including
immunity, cell death, and cell membrane homeostasis.
Gene targeted mice with a null mutation of Pla2g6
develop the INAD phenotype as late as approximately 1
to 2 years after birth. Recently, another INAD mouse
model, Pla2g6-INAD mice line, has been established.
The Pla2g6-INAD mice bear a point mutation in the
ankyrin repeat domain of Pla2g6 generated by N-ethylN-nitrosourea
mutagenesis. These mutant mice develop
severe motor dysfunction and hematopoietic abnormality
in a manner following Mendelian law. The mice showed
the abnormal gait and poor performance as early as 7 to
8 weeks of age, detected by hanging grip test.
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. When analyzed the offspring which
bear Pla2g6 knockout allele and Pla2g6-INAD allele,
abnormal gait appeared slightly later than Pla2g6-INAD
homozygotes but with earlier onset than the Pla2g6
knockout homozygotes. This result suggests that mutant
Pla2g6 protein contributes to early onset of INAD
symptoms in the absence of intact Pla2g6 protein. The
analysis of various INAD mouse models may help to
understand the pathogenesis of neurodegenerative
diseases, including INAD.
Citation
Histology and Histopathology, vol. 28, nº 8 (2013)
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