Lysosomal lipid storage diseases

Abstract

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.

Figure 1.

Structures of ganglioside GM2, sphingomyelin, ceramide, and BMP.

Figure 2.

Degradation of selected sphingolipids in the lysosomes of the cells. The eponyms of individual inherited diseases are given. Activator proteins required for the respective degradation step in vivo are indicated. Variant AB, AB variant of GM2 gangliosidosis (deficiency of GM2-activator protein); Sap, saposin (adapted from Kolter and Sandhoff [2005] and reprinted here with permission from Annual Review of Cell and Developmental Biology ©2005).

Figure 3.

Model of endocytosis and lysosomal digestion of membranes. Glycosphingolipids (GSL) are highlighted on the plasma membrane (PM) and on internal membranes, and gradients of pH in the lumen of the organelles and lipids in the intraendolysosomal vesicles; cholesterol (Chol), BMP, sphingomyelin (SM; hypothetical), and ceramide (Cer; hypothetical) are shown (adapted from Kolter and Sandhoff [2005] and reprinted here with permission from Annual Review of Cell and Developmental Biology ©2005). EGFR epidermal growth factor receptor, SAP sphingolipid activator proteins.

Figure 4.

Proposed model for lipid sorting at the stage of late endosomes. At the surface of intraendosomal vesicles acid sphingomyelinase degrades sphingomyelin to ceramide. The resulting decrease of sphingomyelin and the increase of ceramide levels stimulate the removal of cholesterol from BMP containing inner endosomal vesicles and its transfers to NPC1 in the limiting membrane of the late endosome (Infante et al. 2008). NPC1 mediates cholesterol egress through the glycocalyx (adapted from Abdul-Hammed et al. [2010] and reprinted with permission from the American Society for Biochemisty and Molecular Biology ©2010).