The function of sphingolipids in the nervous system: lessons learnt from mouse models of specific sphingolipid activator protein deficiencies

Abstract

We have generated specific saposin A and D deficient mouse mutants by the gene targeting technology. Saposin A deficient mice showed the clinical, biochemical and pathological phenotype of a chronic form of globoid cell leukodystrophy (Krabbe disease) establishing that saposin A is essential for in vivo degradation of galactosylceramide. Saposin D deficient mice showed an accumulation of ceramides containing a-hydroxy fatty acids (HFA/d18:1) in the brain and kidney and showed renal tubular degeneration and cerebellar Purkinje cell loss. Here we review the current information which we have learnt from these mouse models of specific sphingolipid activator protein deficiencies. Collectively, the information provides support for the potential importance of sphingolipids in the function of the nervous system.

Normal phase liquid chromatography coupled to quadrupole time of flight atmospheric pressure chemical ionization mass spectrometry for separation, detection and mass spectrometric profiling of neutral sphingolipids and cholesterol

“…Moreover, neutral SLs have been reported to be altered in many other disorders such as cancer, metabolic syndrome, insulin resistance, cystic fibrosis, and Alzheimer disease [9][10][11][12]. In this context, many studies based on genetic engineering or treatment with pharmacological agents have been performed to investigate different aspects of the biochemical pathway related to the turnover of neutral SLs as well as to their interplay with cholesterol (Chol) [13][14][15][16][17][18]. In this respect, analysis of SLs and GSLs in combination with Chol from cells and tissues by means of modern analytical tools is essential.…”

Mesotrypsin and Caspase-14 Participate in Prosaposin Processing

“…It has been established that deficiency or dysfunction of prosaposin or saposins can result in lysosomal storage disorders that can be mimicked by deficiency of the enzyme activated by the particular saposin(s) involved (14,17). Total deficiency of human or mouse prosaposin results in aberrant storage of multiple glycosphingolipids in a variety of organs (33).…”

“…Saposins are sphingolipid activator proteins that are derived from a single precursor, prosaposin. Discovery of inherited diseases associated with saposin deficiency clearly revealed the essential role of these molecules in sphingolipid metabolism (16,17). Although each of the saposins is generated by limited proteolysis of prosaposin, the processing enzyme(s) in the epidermis have not yet been identified.…”

Monogenic neurological disorders of sphingolipid metabolism

“…However, a doubly deficient mouse, obtained by breeding twitcher and saposin A-deficient mice, presented with more severe neurological symptoms than twitcher mice, and widespread neuronal cell death mainly affecting the hippocampus, but also the cerebral cortex. The brain of these mice showed much greater accumulation of lactosylceramide than the twitcher mice, suggesting that lactosylceramide could contribute to the hippocampal neuronal formation and maintenance [93].…”