The high concentration of
N-acetylaspartate (NAA) in neurons of the central nervous system and its growing clinical use as an
indicator of neuronal viability has intensified interest in the
biological function of this
amino acid derivative. The biomedical relevance of such inquiries is highlighted by the myelin-associated pathology of
Canavan disease, an inherited childhood disorder resulting from mutation of
aspartoacylase (ASPA), the NAA-hydrolyzing
enzyme. This
enzyme is known to be localized in oligodendrocytes with bimodal distribution in cytosol and the myelin sheath, and to produce acetyl groups utilized in myelin
lipid synthesis. Loss of this acetyl source in
Canavan disease and rodent models such as the
tremor rat are thought to account for the observed myelin deficit. This study was undertaken to further define and quantify the specific
lipid abnormalities that occur as a result of ASPA deficit in the
tremor rat. Employing mass spectrometry together with high performance thin-layer chromatography, we found that myelin from 28-day-old animals showed major reduction in
cerebrosides (CB) and
sulfatides (Sulf) with unsubstituted
fatty acids, and equal if not greater changes in myelin from 7-month-old
tremors.
Cerebrosides with 2-hydroxyfatty
acids showed little if any change at either age; Sulf with 2-hydroxyfatty
acids showed no significant change at 28 days, but surprisingly a major increase at 7 months. Two species of
phosphatidylcholine, 32:0 and 34:1, also showed significant increase, but only at 28 days. One form of
phosphatidylethanolamine, PE36:1, was reduced a modest amount at both ages, whereas the
plasmalogen form did not change. The dysmyelination that results from inactivation of ASPA is thus characterized by selective decreases as well as some increases in specific
lipids.