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Publication : NAAG synthetase deficiency has only low influence on pathogenesis in a Canavan disease mouse model.

First Author  Becker I Year  2024
Journal  J Inherit Metab Dis Volume  47
Issue  2 Pages  230-243
PubMed ID  38011891 Mgi Jnum  J:348902
Mgi Id  MGI:7644022 Doi  10.1002/jimd.12693
Citation  Becker I, et al. (2024) NAAG synthetase deficiency has only low influence on pathogenesis in a Canavan disease mouse model. J Inherit Metab Dis 47(2):230-243
abstractText  Canavan disease (CD) is a leukodystrophy caused by mutations in the N-acetylaspartate (NAA) hydrolase aspartoacylase (ASPA). Inability to degrade NAA and its accumulation in the brain results in spongiform myelin degeneration. NAA is mainly synthesized by neurons, where it is also a precursor of the neuropeptide N-acetylaspartylglutamate (NAAG). Hydrolysis of this peptide by glutamate carboxypeptidases is an additional source of extracellular NAA besides the instant neuronal release of NAA. This study examines to what extent NAA released from NAAG contributes to NAA accumulation and pathogenesis in the brain of Aspa(nur7/nur7) mutant mice, an established model of CD. Towards this aim, Aspa(nur7/nur7) mice with additional deficiencies in NAAG synthetase genes Rimklb and/or Rimkla were generated. Loss of myelin in Aspa(nur7/nur7) mice was not significantly affected by Rimkla and Rimklb deficiency and there was also no obvious change in the extent of brain vacuolation. Astrogliosis was slightly reduced in the forebrain of Rimkla and Rimklb double deficient Aspa(nur7/nur7) mice. However, only minor improvements at the behavioral level were found. The brain NAA accumulation in CD mice was, however, not significantly reduced in the absence of NAAG synthesis. In summary, there was only a weak tendency towards reduced pathogenic symptoms in Aspa(nur7/nur7) mice deficient in NAAG synthesis. Therefore, we conclude that NAAG metabolism has little influence on NAA accumulation in Aspa(nur7/nur7) mice and development of pathological symptoms in CD.
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