title: Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease.
abstract: Canavan disease is an early onset leukodystrophy associated with psychomotor retardation, seizures, and premature death. This disorder is caused by mutations in the gene encoding the enzyme aspartoacylase (ASPA). Normally, ASPA is enriched in oligodendrocytes and ASPA deficiency results in elevated levels of its substrate molecule, N-acetylaspartate (NAA), brain edema, and dysmyelination. Using adeno-associated virus, we permanently expressed ASPA in CNS neurons of the tremor rat, a genetic model of Canavan disease, and examined the efficacy of the treatment by monitoring NAA metabolism, myelination, motor behavior, and seizures. Assessment of ASPA protein and enzyme activity in whole brain hemispheres showed restoration to normal levels as long as 6 months after treatment. This finding correlated with a reduction of NAA levels, along with a rescue of the seizure phenotype. However, gross brain pathology, such as dilated ventricles and spongiform vacuolization, was unchanged. Moreover, hypomyelination and motor deficits were not resolved by ASPA gene transfer. Our data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression.
authors.affiliation: Laboratory of Functional Genomics and Translational Neuroscience, Department of Molecular Medicine and Pathology, University of Auckland School of Medicine, 85 Park Road, Auckland, New Zealand. m.klugmann@uni-hd.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Claudia B
authors.initials: CB
authors.lastname: Leichtlein
authors.forename: C Wymond
authors.initials: CW
authors.lastname: Symes
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.forename: Deborah
authors.initials: D
authors.lastname: Young
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D017825:Canavan Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002490:Central Nervous System / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D008297:Male; D009046:Motor Neurons / Q000201:enzymology* / Q000473:pathology*; D009186:Myelin Sheath / Q000378:metabolism; D051381:Rats; D012640:Seizures / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology
chemical_list: D001224:Aspartic Acid; C000179:N-acetylaspartate; D000581:Amidohydrolases; C019751:aspartoacylase