Glycolipid Trafficking in<i>Drosophila</i>Undergoes Pathway Switching in Response to Aberrant Cholesterol Levels

Hortsch, Ralf; Lee, Esther; Nandanan, E.; Hebbar, Sarita; Steinert, Steffen; Lee, Jun Yu; Chua, Doreen See Kin; Kraut, Rachel

doi:10.1091/mbc.e09-01-0005

Cited by 21 publications

(37 citation statements)

References 53 publications

(90 reference statements)

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“…This is the case in this study, where the cholesterol and sphingomyelin levels in diseased cells directly related to the level of caveolar dysfunction. This agrees with previous studies showing aberrant trafficking of lactosylceramide and ganglioside ligands in these diseases (associated with caveolae), which were rerouted from a Golgi-targeting pathway to a lysosomal route 23, 24 . Others have also reported disruption of caveolar microdomains in a Batten disease model and poor recruitment of signaling molecules to lipid rafts in a Krabbe’s disease model 25, 57 .…”

Section: Discussionsupporting

confidence: 93%

“…sequestration of endocytic machinery, compartment mistrafficking, altered signaling, etc.). Specifically, vesiculation and vesicle trafficking depends on membrane lipid composition, of which cholesterol and other lipid raft constituents, such as sphingomyelin, are key regulatory components 24, 53, 54 . Therefore, we examined the relative levels of cholesterol and sphingomyelin in these LSD cells.…”

Section: Resultsmentioning

confidence: 99%

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A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders

et al. 2016

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Many cellular activities and pharmaceutical interventions involve endocytosis and delivery to lysosomes for processing. Hence, lysosomal processing defects can cause cell and tissue damage, as in lysosomal storage diseases (LSDs) characterized by lysosomal accumulation of undegraded materials. This storage causes endocytic and trafficking alterations, which exacerbate disease and hinder treatment. However, there have been no systematic studies comparing different endocytic routes or LSDs. Here, we used genetic and pharmacological models of four LSDs (type A Niemann-Pick, type C Niemann-Pick, Fabry, and Gaucher diseases) and evaluated the pinocytic and receptor-mediated activity of the clathrin-, caveolae-, and macropinocytic routes. Bulk pinocytosis was diminished in all diseases, suggesting a generic endocytic alteration linked to lysosomal storage. Fluid-phase (dextran) and ligand (transferrin) uptake via the clathrin route were lower for all LSDs. Fluid-phase and ligand (cholera toxin B) uptake via the caveolar route were both affected, but less acutely in Fabry or Gaucher diseases. EGF-induced macropinocytosis was altered in Niemann-Pick cells, not other LSDs. Intracellular trafficking of ligands was also distorted in LSD vs. wild-type cells. The extent of these endocytic alterations paralleled the level of cholesterol storage in disease cell lines. Confirming this, pharmacological induction of cholesterol storage in wild-type cells disrupted endocytosis, and model therapeutics restored uptake in proportion to their efficacy in attenuating storage. This suggests a proportional and reversible relationship between endocytosis and lipid (cholesterol) storage. By analogy, the accumulation of biological material in other diseases, or foreign material from drugs or their carriers, may cause similar deficits, warranting further investigation.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders

et al. 2016

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“…For example, patient fibroblasts and Drosophila models of LSDs have altered trafficking of a lactosylceramide analog, a plasmalemma lipid internalized by a “caveolar-like” route, 25, 48 . CTB is re-routed to endosomes rather than the Golgi apparatus in fibroblasts from four LSDs 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent work using neuronal ceroid lipofuscinosis models have also demonstrated endocytic dysfunctions, despite genetic and lysosomal storage profiles different from NPD 58, 59 . Numerous factors may play a role, such as cytoskeletal abnormalities, impaired cytosolic diffusion of molecules, and/or altered lipid metabolism 19, 20, 22, 25, 48, 60 . In particular, NPD-associated changes of the lipid composition (sphingomyelin and cholesterol 26 ) in membranes along the biosynthetic and endocytic routes could disrupt the biophysical properties of lipid raft domains and other regions, altering the association of integral and peripheral proteins that act as receptors, adaptors, signaling molecules, and others.…”

Section: Discussionmentioning

confidence: 99%

Altered Clathrin-Independent Endocytosis in Type A Niemann-Pick Disease Cells and Rescue by ICAM-1-Targeted Enzyme Delivery

et al. 2015

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Pharmaceutical intervention often requires therapeutics and/or their carriers to enter cells via endocytosis. Therefore, endocytic aberrancies resulting from disease represent a key, yet often overlooked, parameter in designing therapeutic strategies. In the case of lysosomal storage diseases (LSDs), characterized by lysosomal accumulation of undegraded substances, common clinical interventions rely on endocytosis of recombinant enzymes. However, the lysosomal defect in these diseases can affect endocytosis, as we recently demonstrated for clathrin-mediated uptake in patient fibroblasts with type A Niemann-Pick disease (NPD), a disorder characterized by acid sphingomylinase (ASM) deficiency and subsequent sphingomyelin storage. Using similar cells, we have examined if this is also the case for clathrin-independent pathways, including caveolae-mediated endocytosis and macropinocytosis. We observed impaired caveolin-1 enrichment at ligand-binding sites in NPD vs. wild type fibroblasts, corresponding with altered uptake of ligands and fluid-phase markers by both pathways. Similarly, aberrant lysosomal storage of sphingomyelin induced by pharmacological means also diminished uptake. Partial degradation of the lysosomal storage by untargeted recombinant ASM lead to partial uptake enhancement, while both parameters were restored to wild type levels by ASM delivery using model polymer nanocarriers specifically targeted to intercellular adhesion molecule-1 (anti-ICAM NCs). Carriers also restored caveolin-1 enrichment at ligand-binding sites and uptake through the caveolar and macropinocytic routes. These results demonstrate a link between lysosomal storage in NPD and alterations in clathrin-independent endocytosis, which could apply to other LSDs. Hence, this study shall guide the design of therapeutic approaches using viable endocytic pathways.

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“…Surprisingly, study of lipid storage and trafficking models in Drosophila, shows that cholesterol storage alters the trafficking of a glycolipid from the biosynthetic to the degradative endolysosomal pathway and cholesterol depletion eliminates glycolipid recycling. Lactosyl ceramide diverts a neutral cargo (dextran) away from the lysosome (Hortsch et al 2010).…”

Section: Lipid Homeostasis and Traffickingmentioning

confidence: 99%

Golgi Glycosylation and Human Inherited Diseases

Freeze¹,

Ng²

2011

Cold Spring Harbor Perspectives in Biology

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Glycolipid Trafficking inDrosophilaUndergoes Pathway Switching in Response to Aberrant Cholesterol Levels

Cited by 21 publications

References 53 publications

A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders

A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders

Altered Clathrin-Independent Endocytosis in Type A Niemann-Pick Disease Cells and Rescue by ICAM-1-Targeted Enzyme Delivery

Golgi Glycosylation and Human Inherited Diseases

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