RRC ID 136
Author Klugmann M, Leichtlein CB, Symes CW, Serikawa T, Young D, During MJ.
Title Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease.
Journal Mol. Ther.
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.
Volume 11(5)
Pages 745-53
Published 2005-5
DOI 10.1016/j.ymthe.2005.01.006
PII S1525-0016(05)00013-4
PMID 15851013
MeSH Amidohydrolases / deficiency Amidohydrolases / genetics Amidohydrolases / metabolism* Animals Aspartic Acid / analogs & derivatives* Aspartic Acid / metabolism Canavan Disease / enzymology* Canavan Disease / genetics Canavan Disease / pathology* Canavan Disease / physiopathology Central Nervous System / enzymology Central Nervous System / pathology* Central Nervous System / physiopathology Dependovirus / genetics Disease Models, Animal* Female Gene Expression Male Motor Neurons / enzymology* Motor Neurons / pathology* Myelin Sheath / metabolism Rats Seizures / enzymology Seizures / metabolism Seizures / physiopathology
IF 7.008
Times Cited 35
Rats TRM/Kyo(strainID=11)