| Sjögren-Larsson syndrome (SLS) is a genetic disease characterized by ichthyosis and neurologic symptoms due to defective fatty aldehyde dehydrogenase (FALDH). Impaired fatty aldehyde oxidation in SLS results in formation of aldehyde adducts, including N-alkyl-phosphatidylethanolamine (NAPE). Subcellular fractionation studies of fibroblasts from SLS patients found that NAPE accumulated preferentially in the endoplasmic reticulum, which is the site where FALDH is located. Incubation of fibroblast homogenates with [3H]-octadecanal resulted in the spontaneous formation of [ 3H]-NAPE to an equal extent in SLS and normal cells. However, intact SLS fibroblasts synthesized NAPE at a 12-fold greater rate than normal when grown in the presence of octadecanal. SLS fibroblasts had a faster rate of NAPE turnover than normal cells. However, this turnover rate was directly proportional to the cellular NAPE content. When NAPE levels in normal and SLS fibroblasts were equalized (590 pmol/mg protein), the rates of NAPE turnover (50 pmol/mg protein/day) were the same in both cell lines. PE turnover was also similar in normal and SLS cells (8 nmol/mg protein/day). These results indicate that SLS fibroblasts accumulate NAPE due to an increased biosynthetic rate associated with excess fatty aldehyde. When intact cultured fibroblasts were treated with [3H]-NAPE, a new lipid appeared, demonstrating that NAPE was metabolized. Furthermore, a phospholipase D inhibitor, wortmannin, interfered with NAPE turnover, implicating this enzyme in NAPE catabolism. Fatty aldehyde generated from the endogenous metabolism of phytanic acid, fatty alcohol, and sphingosine increased NAPE accumulation in SLS fibroblasts. Competitive adduct inhibitors, such as L-carnosine or cysteamine, reduced NAPE formation from aldehydes generated by oxidation of octadecanol by up to 80% and 76%, respectively.; To understand the white matter disease in SLS, formation of NAPE and aldehyde-protein adducts were studied in mouse myelin. In myelin, [ 3H]-octadecanal formed adducts with lipid (>90%) and protein (<10%). The major aldehyde-lipid adduct was NAPE, whereas another potential adduct (plasmalogalactosylceramide) was not detected. Using Western analysis and immunoprecipitation techniques, myelin basic protein accounted for 34 ± 9% of total protein adducts. These studies implicate fatty aldehyde adduct formation in the pathogenesis of SLS and suggest new approaches for the therapy of this disease. |
