DHA SYNTHESIS AND TRANSPORT IN PEX2-/-MOUSE

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DESCRIPTION: (Adapted from the applicant's Description) This study will focus on the metabolism of docosahexaenoic acid (22:6n-3,DHA) in the brain and liver of the PEX2 -/- mouse, a model of the human peroxisome biogenesis disorder Zellweger syndrome (ZS). The PEX2 -/- mouse has abnormal neuronal migration and biochemical defects similar to those in human ZS. Normally 22:6n-3 is present in high concentration in brain and retina. It is derived in part from the diet and also by endogenous synthesis from linolic acid (18:3n-3) by a series of desaturation and elongation steps. Although most of these reactions take place in microsomes, recent studies indicate that the peroxisome also plays a key role. Studies in clutured skin fibroblasts indicate that 24:6n-3 is the immediate precursor of 22:6n-3, that this final chain shortening step takes place in the peroxisome, and that this step is deficient in fibroblasts of ZS patients. 22:6n-3 levels are reduced in the brain, liver, erythrocytes and plasma of ZS patients. Oral 22:6n-3 administration normalizes plasma levels and anecdotal reports suggest that it improves brain and retinal fuction. The investigators' preliminary studies have demonstrated 22:6n-3 deficiency in the brain of the PEX2-/- mouse. They proposed to examine the mechanism of this reduction by comparing 22:6n-3 synthesis and 22:6n-3 transport into the brain in PEX2 -/- mice and control littermates. Synthesis will be studied in vivo by measuring the labeling of 22:6n-3 after intraperitioneal and intracranial injections of the remote precursor [1-14C] 18:3n-3 and of [1-14C] 22:5n-3, the most direct precursor that is commercially available. Comparison of results of intraperitioneal and intracranial injection will permit assessment of transport. In vivo studies will be complemented by in vitro homogenate studies with the same radiolabled precursors. Studies of 22:6n-3 metabolism in the brain of the PEX2 -/- mouse provide the opportunity to evaluate the role of 22:6n-3 deficiency in ZS and the potential benefit for therapeutic intervention.