? DESCRIPTION (provided by applicant): Canavan disease is a recessively inherited disorder caused by inactivating aspartoacylase (ASPA) mutations and characterized by forebrain, cerebellar, and brainstem vacuolar degeneration, astrogliosis, and dysmyelination (spongiform leukodystrophy). No treatments for children with Canavan disease have yet proven effective. ASPA is an oligodendroglial enzyme that cleaves N-acetyl-L-aspartate (NAA), releasing acetate and L-aspartate. NAA is synthesized by the neuronal enzyme N-acetyltransferase-8 like (NAT8L), and is maintained at approximately 10mM in the normal CNS, but in Canavan disease, CNS NAA climbs far above that level. A popular hypothesis is that acetate released from NAA and converted to acetyl-CoA by oligodendroglial acetyl-CoA synthetase is essential to maintain the oligodendroglial lipogenic acetyl-CoA pool, and that spongiform leukodystrophy in Canavan disease is attributable to oligodendroglial acetyl-CoA starvation. But our preliminary data challenge the necessity for NAA-derived acetate for CNS myelin lipid synthesis by showing that, in the CNS of homozygous constitutive NAT8L knockout (NAT8LKO/KO) mice, in which NAA is undetectable by 1H-magnetic resonance spectroscopy, acetyl-CoA content and myelination are normal. Specific Aim 1 will evaluate an alternative hypothesis, that spongiform leukodystrophy in Canavan disease is a consequence of persistently elevated CNS concentrations of NAA. We will employ a well characterized mouse Canavan model caused by homozygosity for a nonsense ASPA mutation (ASPAnur7). By crossing mice carrying ASPAnur7 and NAT8LKO alleles, ASPAnur7/nur7 mice carrying 2, 1, or 0 NAT8LKO alleles will be generated, and will be used to test the prediction that suppressing NAA synthesis in ASPAnur7/nur7 mice will prevent spongiform leukodystrophy. In Specific Aim 2, we will administer tamoxifen to symptomatic young adult ASPAnur7/nur7 mice that are homozygous for a conditional NAT8L allele (NAT8Lflox) and carrying a widely expressed tamoxifen-inducible cre transgene to test whether delayed suppression of NAA synthesis will reverse their pre-existing spongiform leukodystrophy. If so, interventions to prevent elevated CNS NAA levels in children with Canavan disease may be of therapeutic value.
|Effective start/end date||7/15/15 → 6/30/17|
- National Institutes of Health: $196,250.00
- National Institutes of Health: $234,750.00