Adrenoleukodystrophy (X-ALD) is a X-linked peroxisomal disorder which leads to neurological degeneration and is characterized by pathognomonic accumulation of saturated very long chain (SVLC) fatty acids (>C22) at peaks of C24:0 to C26:0. The normal oxidation of lignoceroyl-CoA as compared to deficient oxidation of lignoceric acid and deficient activity of lignoceroyl-CoA ligase in X-ALD peroxisomes and normalization of lignoceric acid oxidation by supplementation of X-ALD peroxisomes with lignoceroyl-CoA ligase clearly demonstrates that this pathognomonic accumulation of VLC fatty acids in X-ALD is due to impaired activity of peroxisomal VLC (Lignoceric acid) acylCoA ligase. The objectives of this proposal are to further understand the molecular basis of the abnormality in the peroxisomal metabolism of VLC fatty acids and the mechanism of demyelination in X-ALD. Achievement of these goals will be facilitated by the isolation of a c-DNA corresponding to the peroxisomal lignoceroyl-CoA ligase gene, chromosomal localization of the gene for lignoceroyl-CoA ligase and sequence analysis of cDNA from control and X-ALD tissues. Antibodies will be used to study levels of lignoceroyl-CoA ligase in X-ALD tissues and c-DNA will be used to measure the level of m-RNA in X-ALD tissues. The assembly of protein and lipid constituents into membranes with proper orientation for normal function in the cell is a subject of great interest. Studies concerning the topographical localization and transport of unsaturated (nervonic acid) and alpha-hydroxylated (alpha-hydroxylignoceric and alpha-hydroxynervonic acids) fatty acids as compared to lignoceric acid will provide information regarding the metabolic pathways of VLC fatty acids. The possible role of the pathognomically accumulated lipids (lipids containing SVLC fatty acids) in the process of demyelination will be examined by investigating their metabolism in peroxisomes from brain and modulation of the peroxisomal fatty acid metabolic pathway. These proposed studies will provide a better understanding of the normal metabolism of fatty acids in peroxisomes and will help elucidate the molecular interrelationships between abnormal peroxisomal lignoceroyl-CoA ligase activity and its pathological manifestations in X-ALD.
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