title: Suppressing N-Acetyl-l-Aspartate Synthesis Prevents Loss of Neurons in a Murine Model of Canavan Leukodystrophy.
abstract: 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 AspaNur7/Nur7mice. This neuronal pathology is prevented by constitutive disruption of Nat8l, which encodes the neuronal NAA-synthetic enzyme N-acetyltransferase-8-like.
  
  
  
  This is the first demonstration of cortical and cerebellar neuron depletion and progressive cerebral cortical thinning in an animal model of Canavan disease. Genetic suppression of N-acetyl-l-aspartate (NAA) synthesis, previously shown to block brain vacuolation in aspartoacylase-deficient mice, also prevents neuron loss and cerebral cortical atrophy in these mice. These results suggest that lowering the concentration of NAA in the brains of children with Canavan disease would prevent or slow progression of neurological deficits.
authors.affiliation: Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California 95817, and.
authors.forename: Jiho
authors.initials: J
authors.lastname: Sohn
authors.affiliation: Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California 95817, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Bannerman
authors.affiliation: Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California 95817, and.
authors.forename: Fuzheng
authors.identifier: 0000-0003-3410-8389
authors.initials: F
authors.lastname: Guo
authors.affiliation: Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California 95817, and.
authors.forename: Travis
authors.initials: T
authors.lastname: Burns
authors.affiliation: Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California 95817, and.
authors.forename: Laird
authors.initials: L
authors.lastname: Miers
authors.affiliation: Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California 95817, and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Croteau
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, Ohio 44242.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Singhal
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, Ohio 44242.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: McDonough
authors.affiliation: Institute for Pediatric Regenerative Medicine, University of California, Davis, Sacramento, California 95817, and depleasure@ucdavis.edu.
authors.forename: David
authors.identifier: 0000-0002-9122-1268
authors.initials: D
authors.lastname: Pleasure
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D017825:Canavan Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate
keywords: Canavan disease; N-acetyl-l-aspartate; N-acetyltransferase-8-like; aspartoacylase; myelin; neuron