Acylase II, which catalyzes the removal of the acetyl group from N- acetylaspartate (NAA), has been shown to be at a very low or undetectable level in brain in Canavan's disease(1). This enzyme deficit is accompanied by a large increase in brain levels of NAA. Our working hypothesis is that the pathology associated with Canavan's disease results from the deficit of acylase II and/or the increase in NAA levels. However, the role of NAA in cellular metabolism has not been firmly established, and the effects of elevated brain levels of NAA on cell metabolism are unknown. Thus, the significance of the block in NAA metabolism and increased levels of NAA with respect to the characteristic white matter pathology of Canavan's disease is unknown. The overall goals of this research proposal are: (1) to clarify the role of N-acetylaspartate in cellular metabolism of the brain; (2) to develop a protocol for a rat model with chronically decreased NAA catabolism and elevated brain NAA levels by continuous administration of a new inhibitor of acylase II which we have recently synthesized and shown to be effective in vivo. The inhibitor will be given via an Alzet pump. This will be the first animal model of Canavan's disease; (3) to determine the correspondence of this animal model to Canavan's disease; and (4) to utilize this model to determine the effects of decreased NAA catabolism and elevated brain NAA levels on aspects of brain metabolism. In accomplishing these goals, we will conduct in vivo NMR studies of rat brain NAA which parallel the biochemical studies of NAA described above and use the biochemical data to further clarify the relationship of NMR spectra to brain metabolism in both research and clinical applications.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD029926-04
Application #
2202289
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-04-01
Project End
1997-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Miller, S L; Daikhin, Y; Yudkoff, M (1996) Metabolism of N-acetyl-L-aspartate in rat brain. Neurochem Res 21:615-8