Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia.

For decades, the dopamine hypothesis has gained the most attention in an attempt to explain the origin and the symptoms of schizophrenia. While this hypothesis offers an explanation for the relationship between psychotic symptoms and dopamine kinetics, it does not provide a direct explanation of the etiology of schizophrenia which remains poorly understood. Consequently, current antipsychotics that target neurotransmitter receptors, have limited and inconsistent efficacy. To gain insights into the mechanism of action of these drugs, we studied the expression profile of 12,490 human genes in a cell line treated with 18 antipsychotics, and compared it to that of a library of 448 other compounds used in a variety of disorders. Analysis reveals a common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol, which is discussed in the context of a lipid hypothesis where alterations in lipid homeostasis might underlie the pathogenesis of schizophrenia. This finding may help research aimed at the development of novel treatments for this devastating disease.

Sphingolipid metabolism regulates development and lifespan in Caenorhabditis elegans.

Sphingolipids are a highly conserved lipid component of cell membranes involved in the formation of lipid raft domains that house many of the receptors and cell-to-cell signaling factors involved in regulating cell division, maturation, and terminal differentiation. By measuring and manipulating sphingolipid metabolism using pharmacological and genetic tools in Caenorhabditis elegans, we provide evidence that the synthesis and remodeling of specific ceramides (e.g., dC18:1-C24:1), gangliosides (e.g., GM1-C24:1), and sphingomyelins (e.g., dC18:1-C18:1) influence development rate and lifespan. We found that the levels of fatty acid chain desaturation and elongation in many sphingolipid species increased during development and aging, with no such changes in developmentally-arrested dauer larvae or normal adults after food withdrawal (an anti-aging intervention). Pharmacological inhibitors and small interfering RNAs directed against serine palmitoyl transferase and glucosylceramide synthase acted to slow development rate, extend the reproductive period, and increase lifespan. In contrast, worms fed an egg yolk diet rich in sphingolipids exhibited accelerated development and reduced lifespan. Our findings demonstrate that sphingolipid accumulation and remodeling are critical events that determine development rate and lifespan in the nematode model, with both development rate and aging being accelerated by the synthesis of sphingomyelin, and its metabolism to ceramides and gangliosides.