Jamming the endosomal system: lipid rafts and lysosomal storage diseases

doi:10.1016/S0962-8924(00)01847-X

Trends in Cell Biology

Volume 10, Issue 11, 1 November 2000, Pages 459-462

https://doi.org/10.1016/S0962-8924(00)01847-X Get rights and content

Abstract

Some lysosomal storage diseases result from the accumulation of lipids in degradative compartments of the endocytic pathway. Particularly striking is the example of the Niemann–Pick (NP) syndrome. NP syndromes types A and B are characterized by the accumulation of sphingomyelin, whereas cholesterol typically accumulates in NP type C. These two different lipids, sphingomyelin and cholesterol, are normal constituents of specific lipid microdomains called rafts. Because accumulation of raft lipids is observed not only in NP diseases but also in many other lipidoses, we forward the hypothesis that lysosomal storage diseases can be caused by the accumulation of lipid rafts in late endosomes/lysosomes.

Section snippets

Lysobisphosphatidic acid-rich membranes of late endosomes

One lipid that is enriched in late endosomes is lysobisphosphatidic acid (LBPA), which is a characteristic molecule of this degradative organelle in the endocytic pathway¹⁵. LBPA is localized to the complex system of membranes present in the lumen of late endosomes and is an abundant constituent of these membranes (4–17 mole percent)¹⁵. A unique property of LBPA is that the lipid is a poor substrate for phospholipases and hence is resistant to lysosomal enzyme degradation¹⁶. The lipid is

Lipid storage diseases

A relatively large subgroup of lysosomal storage diseases are caused by the accumulation of lipids in late endosomes or lysosomes21., 22.. The Niemann–Pick (NP) syndrome, which is now known to have more than one cause23., 24., is of particular interest; NP types A and B are characterized by sphingomyelin accumulation, whereas cholesterol typically accumulates in the third form, NPC. In NPC, accumulation of cholesterol in degradative compartments of the endocytic pathway is apparently due to a

A unified working hypothesis

These findings led us to formulate a model for the normal handling of lipid rafts in the endocytic pathway, which might serve to clarify some of the problems associated with lipid storage diseases. The basis of our postulate is that the amounts of raft lipids tolerated by late endosomes are limited. In some cell types, with a high hydrolytic capacity, sphingolipids might be transported to late endosomes and then be rapidly degraded after incorporation into LBPA-internal membranes, where the

Perspectives

Beyond the striking similarities in raft lipid redistribution in lipid storage diseases, great variations are observed in the types of affected tissues and in the clinical pictures. These variations might be caused by cell-type-specific expression of sphingolipids, as well as by differences in the residual activity of an affected enzyme (threshold theory), which might lead to an adult (high residual activity) or infantile (low residual activity) onset of the disease (discussed in Ref. 22).

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Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.
Molecular recognition between membrane epitopes and nearly free surface silanols explains silica membranolytic activity
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Inhaled crystalline silica causes inflammatory lung diseases, but the mechanism for its unique activity compared to other oxides remains unclear, preventing the development of potential therapeutics. Here, the molecular recognition mechanism between membrane epitopes and “nearly free silanols” (NFS), a specific subgroup of surface silanols, is identified and proposed as a novel broad explanation for particle toxicity in general. Silica samples having different bulk and surface properties, specifically different amounts of NFS, are tested with a set of membrane systems of decreasing molecular complexity and different charge. The results demonstrate that NFS content is the primary determinant of membrane disruption causing red blood cell lysis and changes in lipid order in zwitterionic, but not in negatively charged liposomes. NFS-rich silica strongly and irreversibly adsorbs zwitterionic self-assembled phospholipid structures. This selective interaction is corroborated by density functional theory and supports the hypothesis that NFS recognize membrane epitopes that exhibit a positive quaternary amino and negative phosphate group. These new findings define a new paradigm for deciphering particle-biomembrane interactions that will support safer design of materials and what types of treatments might interrupt particle-biomembrane interactions.
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Trends in Cell Biology

ForumJamming the endosomal system: lipid rafts and lysosomal storage diseases

Abstract

Section snippets

Lysobisphosphatidic acid-rich membranes of late endosomes

Lipid storage diseases

A unified working hypothesis

Perspectives

J. Biol. Chem.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

Semin. Cell Dev. Biol.

Immunol. Today

Chem. Phys. Lipids

J. Biol. Chem.

Brain Dev.

Lancet

Cell

J. Lipid Res.

Functions of lipid rafts in biological membranes

Annu. Rev. Cell Dev. Biol.

Functional rafts in cell membranes

Nature

Sphingolipid-cholesterol rafts diffuse as small entities in the plasma membrane of mammalian cells

J. Cell Biol.

Cholesterol-dependent retention of GPI-anchored proteins in endosomes

EMBO J.

The recycling endosome of MDCK cells is a mildly acidic compartment rich in raft components

Mol. Biol. Cell

Isolation and biochemical characterization of organelles from the yeast, Saccharomyces cerevisiae

Yeast

Large-scale co-aggregation of fluorescent lipid probes with cell surface proteins

J. Cell Biol.

Forum
Jamming the endosomal system: lipid rafts and lysosomal storage diseases