Study on the relation between chorea-acanthocytosis gene and psychiatric disorders

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Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of caudate nucleus and substantia nigra has been reported in brain pathology. Recently, we have identified the gene, CHAC encoding a novel protein, chorein in which a deletion mutation was found in Japanese CHAC families. In the present study, we have cloned the mouse CHAC cDNA, identified the exon-intron structures of the gene, and then produced a CHAC-model mouse introducing #60-61 exons-deletion corresponding to a human disease mutation by gene-targeting technique. The mice began to show motor disturbance and acanthocytosis after becoming old age. In behavioral observations, locomotor activity expressed as moving distance was significantly decreased, and at social interaction test the contact time was decreased significantly in the model mice. In brain pathology, histochemical observation revealed that neuronal apoptosis and gliosis occurred in the striatum, which lead to the decrease in glutamic acid decarboxylase-immunoreactive neurons and fibers and tyrosine hydroxylase-immunoreactive fibers. In substantia nigra, gliosis was observed especially in the pars reticulata, leading to decrease in tyrosine hydroxylase-immunoreactive neurons, glutamic acid decarboxylase-immunoreactive neurons and fibers and substance P-immunoreactive fibers. These findings are completely consistent with the human results reported elsewhere. The CHAC-model mouse therefore provides a good model system to study the human disease.