International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B14. Accumulation of N-acetyl-L-aspartate Causes Epileptic Seizures and Spongiform Degeneration in the Central Nervous System.

Kazuhiro Kitada1, Tomohide Akimitsu2, Yosuke Shigematsu3, Akira Kondo4, Masashi Sasa2, Tadao Serikawa1.
1Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.;
Department of Pharmacology, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.;
Department of Pediatrics, Fukui Medical University, Fukui 910-1193, Japan.;
Department of Pathology, Nagara Neurological Clinic, Fukuoka 812-0007, Japan.

The tremor rat is a mutant that exhibits absence-like seizure, wild running seizure and spongiform degeneration in the central nervous system (CNS). Here we report the identification of the causative gene tremor (tm) by use of a positional cloning method. To effectively identify the causative gene, a comparative mapping around the tm locus was carried out by reciprocal use of microsatellite markers applicable to both species. By this method, genomic deletion was found within the tm critical region, in which aspartoacylase gene is located. Aspartoacylase is an enzyme that hydrolyzes N-acetyl-L-aspartate (NAA) into aspartate, and its deficiency is known to be Canavan disease, characterized by spongy degeneration in the white matter of CNS. Therefore the gene was considered as a good candidate for the anomaly in the CNS of the tremor rat. Indeed, no aspartoacylase activity was detected in any tissues examined and abnormal accumulation of N-acetyl-L-aspartate (NAA) was shown in the mutant brain. Furthermore, direct injection of NAA into the cerebroventricle of normal rats induced the similar seizures as seen in the tremor rat. More interestingly, a knock-out mouse for aspartoacylase gene was recently established, and it was reported that the mice develop both of spongiform degeneration and clonic seizure. Based on these results above, we concluded that the accumulated NAA in the brain causes characteristic seizures and spongiform degeneration in the CNS.

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