Adrenoleukodystrophy is an x-linked disorder of white matter of the central and peripheral nervous system and adrenal cortex. It is associated with pathognomonic accumulation of very long chain (VLC) fatty acids (greater than C22) in cholesterol esters, sphingolipids and phospholipids. We have recently reported that VLC fatty acids (lignoceric acid, C24) are oxidized mainly and possibly exclusively in peroxisomes. This peroxisomal system for oxidation of VLC fatty acids is defective in adrenoleukodystrophy (ALD). On the other hand, peroxisomal system for oxidation of palmitic acid (C16) is normal thus suggesting that peroxisomes may have two enzyme systems for oxidation of different chain length fatty acids. During this grant period we propose to define the specific enzymatic step of peroxisomal B-oxidation system which is nonfunctional in ALD and we will purify this enzyme from normal tissue. Our preliminary studies suggest that similar to liver, VLC fatty acids in brain are also oxidized in peroxisomes. We will isolate peroxisomes from rat brain and will characterize them with respect to protein and lipid composition. The brain peroxisomal system for oxidation of fatty acids will be characterized with respect to kinetic properties, cofactor and metal ion requirement and substrate specificity. We will also test our hypothesis that myelin membranes from ALD brain are distorted and/or unstable; therefore, are degraded by proteolytic enzymes at a faster rate than the control myelin. The studies outlined in this proposal will provide information about the pathogenic process and the mechanism of demyelination in ALD.
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