Disease relevance of Aspa

• Canavan disease, an autosomal-recessive neurogenetic disorder, is caused by mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to generate free acetate in the brain [1].
• Normally, ASPA is enriched in oligodendrocytes and ASPA deficiency results in elevated levels of its substrate molecule, N-acetylaspartate (NAA), brain edema, and dysmyelination [2].
• PURPOSE: We previously reported that an increase in the N-acetyl-L-aspartate (NAA) level due to the lack of aspartoacylase gene was found in the brain of the tremor rat (tm/tm), which is a mutant with a causative gene named tm that shows epileptic seizures [3].
• Recombinant adenovirus (5x10(7) pfu) carrying the rat ASPA gene (AxASPA) or beta-galactosidase gene (AxLacZ), as a control virus, was intracerebroventricularly administered to premature tremor rats aged 7 weeks [4].
• The absence of aspartoacylase activity in Canavan disease (CD), a rare early onset genetic spongiform leukodystrophy, is associated with CNS edema, intramyelinic swelling and a progressive loss of oligdendrocytes [5].

High impact information on Aspa

• Our data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression [2].
• Using adeno-associated virus, we permanently expressed ASPA in CNS neurons of the tremor rat, a genetic model of Canavan disease, and examined the efficacy of the treatment by monitoring NAA metabolism, myelination, motor behavior, and seizures [2].
• Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease [2].
• Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase [6].
• To investigate the possible function of NAA, we determined the anatomical, developmental and cellular distribution of aspartoacylase, which catalyses the hydrolysis of NAA [7].

Anatomical context of Aspa

• Immunohistochemical localization of aspartoacylase in the rat central nervous system [8].
• Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination [1].
• Earlier studies have shown that aspartoacylase is primarily restricted to myelin synthesizing cells (oligodendroglia) in the CNS [1].
• Aspartoacylase activity increased with time in freshly isolated astrocytes, with significantly higher activity after 15 days in culture [7].
• We conclude that aspartoacylase activity in the developing postnatal brain corresponds with maturation of myelination, and that the cellular distribution is limited to glial cells [7].

Associations of Aspa with chemical compounds

• Aspartoacylase (ASPA; EC 3.5.1.15) catalyzes deacetylation of N-acetylaspartate (NAA) to generate free acetate in the central nervous system (CNS) [8].
• Recently, this animal model has been demonstrated to display a genomic microdeletion within the critical region of tm, where aspartoacylase hydrolyzing N-acetyl-L aspartate (NAA) is located, besides showing the ability to accumulate NAA in the brain [9].

Analytical, diagnostic and therapeutic context of Aspa

• In situ hybridization using a 35S riboprobe based on murine aspartoacylase cDNA was used in this study [1].
• Assessment of ASPA protein and enzyme activity in whole brain hemispheres showed restoration to normal levels as long as 6 months after treatment [2].
• Adenoviral gene transfer of aspartoacylase into the tremor rat, a genetic model of epilepsy, as a trial of gene therapy for inherited epileptic disorder [4].

References