The field of sphingolipid biology has exploded because sphingolipids have been established as important signaling molecules [1-3], as well as critical components of membranes [4-7]. A number of hereditary disorders involving sphingolipid metabolism have also been discovered [8, 9]. Specific sphingolipid species involved in distinct biological processes and disorders have been characterized in association with the hydrophilic head groups. In contrast, the roles of structural diversities in the ceramide portion of sphingolipids remain largely uncharacterized, despite the fact that some modifications are known to have dramatic influences on the bioactivities of sphingolipids. The overall goal of this project is to understand the roles of alpha-hydroxy sphingolipids in myelin biogenesis and function. alpha-Hydroxylation of N-acyl chain is a major modification that occurs during de novo sphingolipid synthesis and is catalyzed by an enzyme called fatty acid alpha-hydroxylase (Fig. 1) [10, 11]. alpha-Hydroxy sphingolipids are formed in certain tissues in mammals, most notably in the nervous tissue [12-17]. In central and peripheral nervous systems, characteristic glycosphingolipids are found in myelin, a multi-layered structure formed by the plasma membrane of oligodendrocytes and Schwann cells. These glycosphingolipids are galactosylceramide and its derivative sulfatide, which are highly alpha-hydroxylated (>50%). Mice that do not produce these glycosphingolipids have dysfunctional myelin and show an abnormal behavioral phenotype and a short lifespan [18-20]. The high degree of alpha-hydroxylation in the essential myelin glycosphingolipids suggests that alpha-hydroxylation plays critical roles for myelin biogenesis and function. This hypothesis is testable by modulating the activity of fatty acid (alpha-hydroxylase, which produces the precursor of alpha-hydroxy sphingolipids (Fig. 1). One approach is to identify the fatty acid alpha-hydroxylase gene and manipulate its expression in mice. To this end, the PI identified potential human and mouse fatty acid alpha-hydroxylase genes, named FAAH. We hypothesize that the FAAH gene encodes the fatty acid alpha-hydroxylase that produces alpha-hydroxy glycosphingolipids in brain, and that lack of this enzyme results in defects in myelin biogenesis and function.
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