Lysosomal Lipid Storage Diseases

Lysosomal lipid storage diseases, or lipidoses, are inherited metabolic disorders in which typically lipids accumulate in cells and tissues. Complex lipids, such as glycosphingolipids, are constitutively degraded within the endolysosomal system by soluble hydrolytic enzymes with the help of lipid binding proteins in a sequential manner. Because of a functionally impaired hydrolase or auxiliary protein, their lipid substrates cannot be degraded, accumulate in the lysosome, and slowly spread to other intracellular membranes. In Niemann-Pick type C disease, cholesterol transport is impaired and unesterified cholesterol accumulates in the late endosome. In most lysosomal lipid storage diseases, the accumulation of one or few lipids leads to the coprecipitation of other hydrophobic substances in the endolysosomal system, such as lipids and proteins, causing a “traffic jam.” This can impair lysosomal function, such as delivery of nutrients through the endolysosomal system, leading to a state of cellular starvation. Therapeutic approaches are currently restricted to mild forms of diseases with significant residual catabolic activities and without brain involvement.Lysosomal lipid storage diseases are a group of inherited catabolic disorders in which typically large amounts of complex lipids accumulate in cells and tissues. Macromolecules such as complex lipids and oligosaccharides are constitutively degraded in the acidic compartments of the cell, the endosomes, and lysosomes, into their building blocks. The resulting catabolites are exported to the cytosol and reused in cellular metabolism. When lysosomal function is impaired because of a defect in a catabolic step, degradation cannot proceed normally and undegraded compounds accumulate. Lysosomal lipid storage diseases comprise mainly the sphingolipidoses, Niemann-Pick type C disease (NPC), and Wolman disease, including the less severe form of this disease, called cholesteryl ester storage. NPC is a complex lipid storage disease mainly characterized by the accumulation of unesterified cholesterol in the late endosomal/lysosomal compartment (Bi and Liao 2010). The sphingolipidoses are caused by defects in genes encoding proteins involved in the lysosomal degradation of sphingolipids (Kolter and Sandhoff 2006). First reports on these diseases were given more than a century ago. Already in 1881, Warren Tay described the clinical symptoms of a disease, which is today called Tay-Sachs disease (Tay 1881). After Christian de Duve discovered the lysosome in 1955 (de Duve 2005), Henri-Géry Hers established the first correlation between an enzyme deficiency and a lysosomal storage disorder (Pompe’s disease) in 1963 (Hers 1963). In the following decades, the enzymes and cofactors deficient in the sphingolipidoses have been identified. Though lysosomal lipid storage diseases have been known for a long time, treatment is only available for a few mild forms of the diseases, such as the adult forms of Gaucher disease (Barton et al. 1991). For several lysosomal storage diseases, therapies like enzyme replacement or bone marrow transplantation are in the clinical trial stage (Platt and Lachmann 2009). For a long time, lysosomal diseases have been considered a problem of superabundance (storage) in which the storage material can slowly spread to other cellular membranes, impairing their function. More recently, it came into focus that massive storage prevents lysosomal functions such as nutrition delivery through the endolysosomal system, leading to a state of cellular starvation. In mouse models of both GM1 and GM2 gangliosidoses iron is progressively depleted in brain tissue. Administration of iron prolonged survival in the diseased mice by up to 38% (Jeyakumar et al. 2009).