X-adrenoleukodystrophy (X-ALD) is an inherited disorder of very long chain (VLC) fatty acid (C22) metabolism that subsequently leads to the secondary manifestation of a neuroinflammatory response, demyelination/ dysmyelination and loss of myelinated axons and oligodendrocytes. The metabolic defect of pathognomonic accumulation of VLC fatty acids, as constituent complex lipids, is due to the deficient activity of VLC acyl-CoA ligase (lignoceroyl-CoA ligase) present in the peroxisomal membranes. The objective of this proposal is to decipher the function of the ALDP (X-ALD gene product) transporter in relation to the metabolism of VLC fatty acids and the elucidation of molecular events in the transition from a metabolic disease to a neuroinflammatory process in X-ALD. Achievement of these goals will be facilitated by cloning and sequencing the cDNA for PMP62, a partner of the ALDP transporter (ALDP-PMP62), and of the function of this transporter in the metabolism of VLC fatty acids. The antibodies and cDNA generated under specific aim I for PMP62 and the cDNA and antibodies against ALDP and lignoceroyl-CoA ligase already available, will be utilized to decipher the functional organization of ALDP, PMP62 and lignoceroyl-CoA ligase in peroxisomes. The possible role of pathologically accumulated lipids (lipids containing VLC fatty acids) in the transition of metabolic disease into a neuroinflammatory disease process observed in X-ALD will be examined by investigating the metabolic derangement induced modulation of brain cells in the neuroinflammatory response and the functions of peroxisomes and oligodendrocytes. The proposed studies will provide a better understanding of the normal metabolism of VLC fatty acids in peroxisomes and will help decipher the molecular relationship between abnormal lignoceroyl-CoA ligase activity with ALDP-PMP62 transporter and the pathological manifestations in X-ALD.
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