Canavan Disease

National Institute Of Mental Health

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Abstract

Canavan disease (CD) is a neurogenetic disorder which is caused by the mutation of an enzyme known as N-aspartoacylase (ASPA) which cleaves N-acetylaspartate (NAA) into acetate and aspartate. ASPA NAA ---------------------------------------------------> ACETATE + ASPARTATE MUTATED IN CD l IN OLIGODENDROGLIA Myelin (fats) CD is characterized by severe mental retardation, degeneration of the brain, and death usually occurs before 10 years of age. On the basis of these and other studies we have proposed that CD results from decreased myelin synthesis during development caused by a deficiency in the supply the NAA-derived acetate, a major source of fatty acids which synthesizes lipids (?fats?) in the brain during development. Myelin is the fatty layer (white matter) that insulates nerves in the brain. The predominant white matter involvement of CD is consistent with this hypothesis. Recent studies have shown that ASPA in the CNS is primarily restricted to myelin synthesizing cells in the CNS known as oligodendroglia. We have previously determined that the developmental expression (appearance) of the ASPA gene closely parallels development of myelin in different regions of the brain. This has provided support for the acetate deficiency hypothesis of CD. More recently, in order to gain insights into the role of ASPA in myelin synthesis, we generated a rabbit antibody against ASPA (obtained from the mouse brain). Immunohistochemical studies revealed that ASPA colocalized with a marker for oligodendrocytes (CC1) throughout the brain. Abundant cells were labeled in white matter such as the corpus callosum and axonal layers of the cerebellum, while relatively lower numbers of cells were labeled in grey matter such as the cerebral cortex. ASPA did not colocalize with GFAP, a marker for astrocytes in the brain. Microglia-like cells showed faint to moderate staining for ASPA. The significance of the relatively lower level of ASPA-immunoreactivity remains unclear, but its predominant localization in oligodendrocytes is consistent with the proposed role of ASPA in myelination, making a strong case for acetate supplementation as an immediate and inexpensive therapy for CD.