Adrenoleukodystrophy (X-ALD) is a X-linked peroxisomal disorder which leads to neurological degeneration and is characterized by accumulation of very long chain (VLC) fatty acids (>C22). It is now demonstrated that this is due to impaired activity of peroxisomal VLC (Lignoceric acid) acyl-CoA ligase. The objectives of this proposal are to further understand the molecular basic of the abnormality in the peroxisomal metabolism of fatty acids and the mechanism of demyelination in X-ALD. this will be facilitated by purification of peroxisomal lignoceroyl-CoA ligase, the generation of polyclonal and monoclonal antibodies against it, and the isolation of a c- DNA will be used to measure the level of m-RNA in X-ALD tissues and the sequence analysis of the protein. The possible role of the pathognomic accumulation of lipids (lipids containing VLC fatty acids) in the process of demyelinization will be examined by investigating the proteolysis of proteins in isolated myelin membranes and synthetic membranes containing ALD lipids. constituents into membranes with the proper orientation for normal function in the cell is a subject of great interest. Studies concerning localization of lignoceroyl-CoA ligase will provide information as to it's topographical localization in the transverse plane of peroxisomal membranes. These studies will provide a better understanding of the normal metabolism of fatty acids in peroxisomes and help elucidate the molecular interrelationship between abnormal peroxisomal lignoceroyl-CoA ligase activity and its pathological manifestations in X-ALD.
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