Gaucher disease is an autosomal recessive lysosomal storage disease caused by a deficiency of glucosylceramidase (β-glucosidase), which results in the abnormal accumulation of glucosylceramide (GlcCer) in tissues. The accumulation of glucosylsphingosine (GlcSph), a derivative of GlcCer devoid of fatty acids, has been demonstrated in the affected tissues of patients with Gaucher disease. The accumulation of GlcSph can be predicted to occur because it is also a substrate of the deficient enzyme, and because the accumulation of the lipid in cells can be demonstrated when the cells are incubated in the presence of inhibitors of glucosylceramidase such as conduritol β epoxide (CBE). Regarding the pathogenesis of Gaucher disease, the accumulation of GlcSph is very important because GlcSph is cytotoxic at very low concentrations like GalSph, while GlcCer is reported to instead stimulate the growth of tissues or cells. In the case of Krabbe disease, a lysosomal storage disease with a deficiency of galactosylceramidase, there is no accumulation of GalCer, while GalSph apparently accumulates in the affected tissues. Similarly, in the tissues in other sphingolipidoses, lysosphingolipids (fatty acid-free sphingolipids) have been shown to accumulate. Data in recent reports have also indicated that lysosphingolipids disturb the mitochondrial function and acylation of the myelin proteolipid protein, and modulate the signal transduction systems in cells. Therefore, it is suggested that the accumulation of lysosphingolipids is apparently related to cell death in sphingolipidoses.
Figure 1. Glucosylsphingosine pathway.
More recently, Sidransky and colleagues reexamined glucosylsphingosine levels in relation to various variants of Gaucher disease. Over the years it has been repeatedly proposed that elevated glucosylsphingosine may underlie some clinical symptoms. For example, recent investigations with cultured osteoblasts of a type 1 Gaucher disease–like mouse model led to the hypothesis that glucosylsphingosine may actively contribute to low bone mineral density by interfering with normal osteoblast function, possibly by altered intracellular calcium homeostasis. In addition, a role for glucosylsphingosine in neurologic symptoms of Gaucher patients has been frequently proposed. Importantly, increased concentrations of other lysoglycosphingolipids have been documented for other lysosomal sphingolipidoses as well, such as galactosylsphingosine (psychosine) in Krabbe disease, and globotriaosylsphingosine (lysoGb3) in Fabry disease, each presumed to play an active role in disease related pathology.
Given the potential biologic significance of glucosylsphingosine, a successful development of a sensitive quantitative detection method is needed. Creative Proteomics provides fast and effective method for quantification of glucosylsphingosine that can satisfy the needs of academic and industrial study in your lab.
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