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Nur7 Is a Nonsense Mutation in the Mouse Aspartoacylase Gene That Causes Spongy Degeneration of the CNS

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Traka, Maria, Wollmann, Robert L., Cerda, Sonia R., Dugas, Jason, Barres, Ben A., Popko, Brian·2008·The Journal of Neuroscience
DOI 10.1523/jneurosci.1490-08.2008PMC PMC2613291
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Abstract

Aspartoacylase (ASPA) is an oligodendrocyte-restricted enzyme that catalyzes the hydrolysis of neuronally derived N-acetylaspartate (NAA) to acetate and aspartic acid. ASPA deficiency leads to the fatal childhood autosomal recessive leukodystrophy Canavan disease (CD). Here we demonstrate that the previously described ENU-induced nur7 mouse mutant is caused by a nonsense mutation, Q193X, in the Aspa gene (Aspa(nur7)). Homozygous Aspa(nur7nur7) mice do not express detectable Aspa protein and display an early-onset spongy degeneration of CNS myelin with increased NAA levels similar to that observed in CD patients. In addition, CNS regions rich in neuronal cell bodies also display vacuolization. Interestingly, distinct myelin rich areas, such as the corpus callosum, optic nerve, and spinal cord white matter appear normal in Aspa(nur7/nur7) mice. Reduced cerebroside synthesis has been demonstrated in CD patients and animal models. To determine the potential relevance of this observation in disease pathogenesis, we generated Aspa(nur7/nur7) mice that were heterozygous for a null allele of the gene that encodes the enzyme UDP-galactose:ceramide galactosyltransferase (Cgt), which is responsible for catalyzing the synthesis of the abundant myelin galactolipids. Despite reduced amounts of cerebrosides, the Aspa(nur7/nur7);Cgt(+/-) mice were not more severely affected than the Aspa(nur7) mutants, suggesting that diminished cerebroside synthesis is not a major contributing factor in disease pathogenesis. Furthermore, we found that myelin degeneration leads to significant axonal loss in the cerebellum of older Aspa(nur7) mutants. This finding suggests that axonal pathology caused by CNS myelin defects may underlie the neurological disabilities that CD patients develop at late stages of the disease.

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  • The nur7 mouse is an (ENU)-induced mutant that has a nonsense point mutation in the ASPA gene, resulting in the absence of functional protein and chronically elevated CNS NAA.

    “The nur7 mouse is an (ENU)-induced mutant that has a nonsense point mutation in the ASPA gene, resulting in the absence of functional protein and chronically elevated CNS NAA.”

    From Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease (2021) · cites this paper as [11]

    The Results section identifies nur7 as an ENU-induced nonsense mutation in Aspa and reports no detectable Aspa protein in mutant mice. It also reports elevated NAA in several CNS regions at postnatal day 21, but does not establish that NAA remains elevated chronically; the NAA analysis described in Methods used mice at that single age. Page numbers are unavailable in our copy. (LLM, conf=0.85)

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  • nur7 pathology is progressive, with deteriorating motor function and CNS cell loss manifest from 2 to 3 weeks of age onward.

    “nur7 pathology is progressive, with deteriorating motor function and CNS cell loss manifest from 2 to 3 weeks of age onward.”

    From Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease (2021) · cites this paper as [11]

    The Results sections on early pathology and disease progression report vacuoles at P14, oligodendrocyte loss in affected CNS regions at P21, and worsening pathology with age. They do not establish deteriorating motor function from 2–3 weeks onward: motor impairment was measured at P42–P56, while severe ataxia is described at later stages. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • nur7 mice present evidence of attempted remyelination in the brain in the form of increased markers of immature oligodendrocytes as late as several weeks of age.

    “nur7 mice present evidence of attempted remyelination in the brain in the form of increased markers of immature oligodendrocytes as late as several weeks of age”

    From Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease (2021) · cites this paper as [11]

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Authors
Traka, M., Wollmann, R. L., Cerda, S. R., Dugas, J., Barres, B. A., & Popko, B.
Affiliations
  • University of Chicago (US)
  • Stanford Medicine (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2008-11-05
Volume
28
Issue
45
Pages
11537-11549
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1490-08.2008
PMC
PMC2613291
OpenAlex
W2051129517
Cited by
82
References
45
Citations by year
2026: 1 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 3 · 2021: 6 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 7 · 2014: 8 · 2013: 7 · 2012: 4
FWCI
3.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • Myelin Repair Foundation
  • Multiple Sclerosis Society
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS027336, R01NS027336)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
aspartoacylase, Canavan disease, nonsense mutation, N-acetylaspartate, cerebrosides, UDP-galactose:ceramide galactosyltransferase, axonal loss, cerebellum, oligodendrocytes, leukodystrophy, ENU-induced mutation
MeSH terms
Age Factors, Amidohydrolases, Animals, Animals, Newborn, Aspartic Acid, Axons, Behavior, Animal, Central Nervous System, Chromosome Mapping, Disease Models, Animal, Glutamine, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Magnetic Resonance Spectroscopy, Oligodendroglia, Canavan Disease, Codon, Nonsense, Disease Progression, Lipid Metabolism, N-Acylsphingosine Galactosyltransferase, Mice

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