Accumulation of N‐Acetyl‐L‐Aspartate in the Brain of the Tremor Rat, a Mutant Exhibiting Absence‐Like Seizure and Spongiform Degeneration in the Central Nervous System

Abstract

Abstract:The tremor rat is a mutant that exhibits absence-like seizure and spongiform degeneration in the CNS. By positional cloning, a genomic deletion was found within the critical region in which the aspartoacylase gene is located. Accordingly, no aspartoacylase expression was detected in any of the tissues examined, and abnormal accumulation of N-acetyl-L-aspartate (NAA) was shown in the mutant brain, in correlation with the severity of the vacuole formation. Therefore, the tremor rat may be regarded as a suitable animal model of human Canavan disease, characterized by spongy leukodystrophy that is caused by aspartoacylase deficiency. Interestingly, direct injection of NAA into normal rat cerebroventricle induced 4-to 10-Hz polyspikes or spikewave-like complexes in cortical and hippocampal EEG, concomitantly with behavior characterized by sudden immobility and staring. These results suggested that accumulated NAA in the CNS would induce neuroexcitation and neurodegeneration directly or indirectly. Key Words: Tremor rats-Epilepsy-Neurodegeneration-Positional cloning-Aspartoacylase -N-Acetyl-L-aspartate. J. Neurochem. 74, 2512Neurochem. 74, -2519Neurochem. 74, (2000.Epilepsy is a diverse neurological abnormality that is characterized by recurrent seizures, affecting 1-2% of the population worldwide (McNamara, 1999). Epileptic seizures comprise alterations in sensory and motor systems and in consciousness. They result from the disordered, synchronous, and rhythmic firing of certain populations of neurons in the CNS. Current therapies are not satisfactory, as they do not provide symptomatic relief in some subsets of affected individuals and are sometimes accompanied by toxic effects. Elucidation of the cellular and molecular mechanisms underlying epileptogenesis, therefore, should lead to the development of new fundamental therapies and prevention methods, or even a cure. Seizure disorders or epilepsy syndromes are presently classified into Ͼ40 distinct types (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Although most epilepsies are considered to be multifactorial diseases, some specific types are considered single-gene disorders (Steinlein et al., 1995;Pennacchio et al., 1996;Biervert et al., 1998;Charlier et al., 1998;Fox et al., 1998;Singh et al., 1998;Wallace et al., 1998;McNamara, 1999).The tremor rat is a single-gene mutant found in the Kyoto:Wistar colony that exhibits absence-like seizure characterized by sudden immobility and staring, simultaneously with the appearance of 5-to 7-Hz spike-wave complexes in cortical and hippocampal EEG (Yamada et al., 1985;Serikawa et al., 1987;Hanaya et al., 1995). Homozygous rats (tm/tm) for the causative genetic locus tremor (tm) exhibit absence-like seizure after the age of 14 weeks, whereas heterozygotes (tm/ϩ) exhibit the same seizure less frequently after 26 weeks (Higashiguchi et al., 1991). In older age groups, wild running and jumping episodes are sometimes observed in tm/tm rats. However, spongiform degene...

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…Despite the established connection between mutations in the gene for ASPA in Canavan disease, and the lost capacity to deacetylate NAA, the specific connection between ASPA deficiency and the failure of proper CNS development remains controversial (Matalon et al, 1995;Matalon and Michals-Matalon, 1998). It has been proposed that lack of deacetylase activity against NAA leads to toxic increases in the concentration of NAA in the brain Kitada et al, 2000;Leone et al, 1999;Leone et al, 2000). The level of extracellular NAA may be a critical factor in determining if it has toxic effects.…”

Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

“…The tremor rat (tm/tm) was first discovered as a genetic mutant in the inbred colony of Kyoto:Wistar rats and was shown to experience spontaneous seizures plus spongiform degeneration in the central nervous system (CNS) [1,2]. The genetic defect in these animals involves deletion of the aspartoacylase (ASPA; N-acetyl-L-aspartate amidohydrolase) gene, a feature that has made it a naturally occurring model of Canavan disease.…”

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease

“…Measurement of elevated NAA levels in urine is used to confirm the diagnosis of CD (24). A mouse knockout model deficient in ASPA activity (13) and a rat model with a natural deletion of the aspartoacylase gene (26) have been recently developed and serve as important tools in understanding biochemical pathologies related to CD (10,(27)(28)(29).…”