Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 2, Pages 413-421Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2013-16.2017
Keywords
aspartoacylase; Canavan disease; myelin; N-acetyl-L-aspartate; N-acetyltransferase-8-like; neuron
Categories
Funding
- NIH [R21NS096004]
- National Multiple Sclerosis Society [RG 5252-A-6]
- Shriners Hospitals for Children
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Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-L-aspartate (NAA) to acetate and L-aspartic acid, elevates brain NAA and causes spongiform vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation. We now report that numbers of cerebral cortical and cerebellar neurons are decreased and that cerebral cortex progressively thins in Aspa(Nur7/Nur7) mice. This neuronal pathology is prevented by constitutive disruption of Nat8l, which encodes the neuronal NAA-synthetic enzyme N-acetyltransferase-8-like.
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