X-linked adrenoleukodystrophy (XALD) is the most common peroxisomal disorder with an incidence of 1:17,000. It is characterized by neurodegeneration and elevated levels of very long-chain fatty acids (VLCFA) in tissues and plasma. The affected genes encodes an ATP binding cassette (ABC) half-transporter (ALDP) that localizes to the peroxisome but has no known function in VLCFA b-oxidation. Previously, we and others have attributed elevated levels of VLCFA to decreased rates of VLCFA beta-oxidation and reduced activity of the enzymes that activated VLCFA to their CoA derivatives, very long acyl-CoA synthetase (VLCS). However, we have recently shown that mice lacking ALDP have increased levels of VLCFAs but normal rates of VLCFA b-oxidation while mice lacking VLCS have reduced rates of VLCFA b-oxidation but normal levels of VLCFAs. This comparison suggests that VLCFA levels are not dependent on VLCFA b-oxidation rates. We will test the hypothesis that ALDP is not directly involved in VLCFA metabolism. The metabolic basis for XALD pathophysiology is generally unknown. Clinically, XALD is highly variable in age of onset, rate of progression and site of initial pathology. Members of single kindreds manifest different forms of XALD and there is no XALD genotype/clinical phenotype or plasma. VLCFA level correlation with clinical phenotype. There is no generally applicable therapy available for XALD. Our long-term goals are to understand the pathophysiology, in part as a model system for genetic influences on neurodegeneration, and to develop a feasible therapy for XALD. In this application, we will use substrate binding, in vitro ATP-hydrolysis assays, and in vivo substrate induction to determine the function of ALD, and use metabolic inhibitors in cultured cells and animal models to test the hypothesis that ALDP mediates interactions between peroxisomes and mitochondria (Aim 1); explore the genetics of CD1-mediated lipid immunity and T cell response in relation to XALD inflammatory demyelination and test the hypothesis that physiologic and/or genetic stress can contribute to disease severity(AIM 2); and evaluate pharmacological approaches to XALD therapy in mouse models of disease (Aim 3).
Showing the most recent 10 out of 167 publications