ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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34 citing papers in PubMed, 52 citations in OpenAlex.
- Oligodendrocyte-targeted adeno-associated virus gene therapy for Canavan disease in children: a phase 1/2 trial.Nature medicine · 2025Trial
- From neuronal marker to metabolic mediator: Expanding the functional landscape of N-acetylaspartate in the central nervous system and the periphery.Neural regeneration research · 2026Article
- Discovery ofACS medicinal chemistry letters · 2026Article
- Substrate translocation and inhibition in human dicarboxylate transporter NaDC3.Nature structural & molecular biology · 2025Article
- Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease.Cell & bioscience · 2024Review
- Astroglial conditional Slc13a3 knockout is therapeutic in murine Canavan leukodystrophy.Annals of clinical and translational neurology · 2024Article
- Developing a human iPSC-derived three-dimensional myelin spheroid platform for modeling myelin diseases.iScience · 2023Article
- Metabolic partitioning in the brain and its hijacking by glioblastoma.Genes & development · 2023Review
- Renewal of oligodendrocyte lineage reverses dysmyelination and CNS neurodegeneration through corrected N-acetylaspartate metabolism.Progress in neurobiology · 2023Article
- The pathogenesis of, and pharmacological treatment for, Canavan disease.Drug discovery today · 2022Review
- AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease.International journal of molecular sciences · 2022Review
- Dual-function AAV gene therapy reverses late-stage Canavan disease pathology in mice.Frontiers in molecular neuroscience · 2022Article
- Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration.Cell stem cell · 2021Article
- Ablating the Transporter Sodium-Dependent Dicarboxylate Transporter 3 Prevents Leukodystrophy in Canavan Disease Mice.Annals of neurology · 2021Article
- The cAMP Inducers ModifyAntioxidants (Basel, Switzerland) · 2021Article
- Inborn disorders of the malate aspartate shuttle.Journal of inherited metabolic disease · 2021Review
- The natural history of Canavan disease: 23 new cases and comparison with patients from literature.Orphanet journal of rare diseases · 2021Article
- Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease.Molecular therapy. Methods & clinical development · 2021Article
- Canavan Disease as a Model for Gene Therapy-Mediated Myelin Repair.Frontiers in cellular neuroscience · 2021Review
- Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies.Frontiers in cellular neuroscience · 2021Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Canavan disease (CD) is a severe, lethal leukodystrophy caused by deficiency in aspartoacylase (ASPA), which hydrolyzes N-acetylaspartate (NAA). In the brains of CD patients, NAA accumulates to high millimolar concentrations. The pathology of the disease is characterized by loss of oligodendrocytes and spongy myelin degeneration in the CNS. Whether accumulating NAA, absence of NAA-derived acetate, or absence of any unknown functions of the ASPA enzyme is responsible for the pathology of the disease is not fully understood. We generated ASPA-deficient (Aspa(nur7/nur7)) mice that are also deficient for NAA synthase Nat8L (Nat8L(-/-)/Aspa(nur7/nur7)). These mice have no detectable NAA. Nevertheless, they exhibited normal myelin content, myelin sphingolipid composition, and full reversal of spongy myelin and axonal degeneration. Surprisingly, although pathology was fully reversed, the survival time of the mice was not prolonged. In contrast, Aspa(nur7/nur7) mice with only one intact Nat8L allele accumulated less NAA, developed a less severe pathology, phenotypic improvements, and, importantly, an almost normal survival time. Therefore, inhibition of NAA synthase is a promising therapeutic option for CD. The reduced survival rate of Nat8L(-/-)/Aspa(nur7/nur7) mice, however, indicates that complete inhibition of NAA synthase may bear unforeseeable risks for the patient. Furthermore, we demonstrate that acetate derived from NAA is not essential for myelin lipid synthesis and that loss of NAA-derived acetate does not cause the myelin phenotype of Aspa(nur7/nur7) mice. Our data clearly support the hypothesis that NAA accumulation is the major factor in the development of CD.
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