Refsum disease (RfD) is an autosomal recessive neurologic disorder of the lipid metabolism. We have identified a novel murine Iona-chain acyl-CoA synthetase (mLACS) associated with the RfD gene using yeast two-hybrid assay. Northern blot analyses revealed that mLA CS was expressed mainly in the brain and testis. mLA CS was highly expressed in the brain at 2 weeks after birth and maintained through adult life. Expressions of the brain-specific LACS family increased in the PC12 cells undergoing neurite outgrowth by nerve growth factor. mLACS preferentially catalyzed the formation of arachidonoyl-CoA more than palmitoyl-CoA or oleoyl-CoA in PC12 cells. Triacsin C, an inhibitor of LACS, suppressed the cell proliferation and decreased mLACS expression in parent PC12 cells. but not in stably anti-sense mLACS cDNA-transfected cells. Our results indicate that mLACS participates in neuronal cell proliferation and differentiation, and interaction of the RfD gene with brain-selective mLACS may be involved in the pathogenesis of RfD. (C) 2003 Elsevier Science (USA). All rights reserved.