N-glycome of the Lysosomal Glycocalyx is Altered in Niemann-Pick Type C Disease (NPC) Model Cells

Kosicek, Marko; Gudelj, Ivan; Horvatić, Anita; Jovic, Tanja; Vučković, Frano; Lauc, Gordan; Hečimović, Silva

doi:10.1074/mcp.ra117.000129

Cited by 30 publications

(21 citation statements)

References 44 publications

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“…This suggests that the glycosylation state of LAMP1 (and LAMP2) may be an important factor in the overall mechanism of cholesterol efflux from the lysosome. A recent study found predominantly complex sialylated N-glycans in purified lysosomes from NPC1-null fibroblasts, in comparison to lysosomes from wild type cells, which had high-mannose N-glycans [9]. Such complexity gives rise to differences in the physico-chemical properties on the inner leaflet of the lysosome e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The cholesterol can then be distributed to other cellular organelles [4,6,7]. The disease affects~1:120,000 births [2] and is classified as a rare lysosomal storage disorder (LSD) [8,9] that ultimately results in early death of the patient.…”

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confidence: 99%

“…The glycan structures form a lining on the inner leaflet of the lysosome, known as the glycocalyx, an approximately 8 nm barrier [15], that can protect the LAMPs and other membrane components of the lysosome from degradation by hydrolytic enzymes [14]. Recently, several studies demonstrate that LAMP1 glycosylation is altered in NPC1 and may contribute to the accumulation of cholesterol and glycosphingolipids [8,9]. Treatment of NPC1 fibroblasts with an inhibitor of O-linked glycosylation, reduced cholesterol storage and increased cholesterol efflux from the cells [8], suggesting that the reduced glycosylation of LAMP1 could be beneficial in reducing the NPC1 disease phenotype.…”

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confidence: 99%

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Abnormal LAMP1 glycosylation may play a role in Niemann-Pick disease, type C pathology

et al. 2020

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A hallmark of Niemann-Pick disease, type C (NPC) is the progressive degeneration of Purkinje neurons in the cerebellum caused by the accumulation of free cholesterol and glycosphingolipids in the lysosome. Recent studies suggest that the state of glycosylation of lysosomal membrane proteins may play a role in disease progression. Our study has identified the presence of a highly glycosylated form of Lysosome Associated Membrane Protein 1 (LAMP1) that correlated spatiotemporally with Purkinje neuron loss. This form of LAMP1 was predominantly localized to activated microglia; showing a~5-fold increase in surface labeling by FACS analysis. This suggests a potential role for LAMP1 in the neuro-inflammatory process in these mice during disease progression. Analysis of other mouse models of neurodegeneration that exhibit neuro-inflammation showed little or no presence of this glycosylated form of LAMP1, suggesting this observation for LAMP1 is specific to NPC disease. Furthermore, early treatment of Npc1 -/mice with 2-hydroxypropyl-β-cyclodextrin (HPβCD), significantly prevented the appearance of the glycosylated LAMP1 in the cerebellum of Npc1 -/mice at 7 weeks, consistent with the prevention of neuro-inflammation in mice treated with this drug. Treatment of Npc1 -/mice with HPβCD at 7 weeks, after disease onset, did not reverse or prevent further appearance of the hyperglycosylated LAMP1, demonstrating that once this aspect of neuro-inflammation began, it continued despite the HPβCD treatment. Analysis of LAMP1 in cerebellar tissue of NPC1 patients showed a small level of hyperglycosylated LAMP1 in the tissue, however, this was not seen in the CSF of patients.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Abnormal LAMP1 glycosylation may play a role in Niemann-Pick disease, type C pathology

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“…Lysosomal morphology and biophysical characteristics under stress of cholesterol storage, such as occurs in NPC1 disease, have been explored and include atypical lysosome buoyancy, abnormal inclusion distributions, increased volume, and altered size . Proteomic analysis revealed alterations in Lamp1 and Lamp2, in the cerebellar and cerebral cortex tissues, respectively, of Npc1 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Quantitative, Label‐Free Proteomics in the Symptomatic Niemann–Pick, Type C1 Mouse Model Using Standard Flow Liquid Chromatography and Thermal Focusing Electrospray Ionization

et al. 2019

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Niemann–Pick disease, type C1 (NPC1) is a fatal, autosomal recessive, neurodegenerative disorder caused by mutations in the NPC1 gene. As a result, there is accumulation of unesterified cholesterol and sphingolipids in the late endosomal/lysosomal system. This abnormal accumulation results in a cascade of pathophysiological events including progressive, cerebellar neurodegeneration, among others. While significant progress has been made to better understand NPC1, the downstream effects of cholesterol storage and the major mechanisms that drive neurodegeneration remain unclear. In the current study, a) the use of a commercial, highly efficient standard flow‐ESI platform for protein biomarker identification is implemented and b) protein biomarkers are identified and evaluated at a terminal time point in the NPC1 null mouse model. In this study, alterations are observed in proteins related to fatty acid homeostasis, calcium binding and regulation, lysosomal regulation, and inositol biosynthesis and metabolism, as well as signaling by Rho family GTPases. New observations from this study include altered expression of Pcp2 and Limp2 in Npc1 mutant mice relative to control, with Pcp2 exhibiting multiple isoforms and specific to the cerebella. This study provides valuable insight into pathways altered in the late‐stage pathophysiology of NPC1.

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“…In agreement with this hypothesis, chloroquine has been previously shown to exert antiviral activity against several caliciviridae through exerting similar inhibitory effect on cathepsin L activity, compared with cathepsin L-specific inhibitors [53], as well as impairing the trimming of the N-glycosylated chain of ACE2, the receptor involved in SARS-CoV and SARS-CoV-2 docking on the host cell membrane [54]. Interestingly, N-glycosylation has been shown to be altered in NPC [55], which further suggests a chloroquine- lysomotropic activity of azithromycin, the add-on therapy combined with hydroxychloroquine in that trial. Interestingly, just like chloroquine, azithromycin has also been shown to accumulate intracellularly within the lysosomes, increasing their luminal pH, and thereby negatively impacting the activity of its resident enzymes [57].…”

Section: Making the Link Between Covid-19 And The Lysosomes Based On mentioning

confidence: 62%

The Lysosome: A Potential Therapeutic Juncture between the COVID-19 Pandemic and Niemann-Pick Type C Disease

Ballout¹

2020

Preprint

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In the face of the newly emergent COVID-19 pandemic, researchers around the world are racing to identify efficacious drugs capable of preventing or treating its infection. They are doing that by testing already available and approved antimicrobials for their rapid repurposing against COVID-19. Using the data emerging on the comparable efficacy of various compounds having different mechanisms of action and indications, I suggest in this report, their potential mechanistic convergence. Specifically, I highlight the lysosome as a key possible therapeutic target for COVID-19, proposing one of the lysosomal storage disorders, Niemann-Pick type C disease (NPC), as a prototypical condition with inherent resistance or an “unfavorable” host cell environment for viral propagation. The included reasoning evolves from previously generated data in NPC, along with the emerging data on COVID-19. The aim of this report is to suggest that pharmacological induction of a “transient” NPC-like lysosomal dysfunction, could hold answers for targeting the ongoing COVID-19 pandemic.

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N-glycome of the Lysosomal Glycocalyx is Altered in Niemann-Pick Type C Disease (NPC) Model Cells

Cited by 30 publications

References 44 publications

Abnormal LAMP1 glycosylation may play a role in Niemann-Pick disease, type C pathology

Abnormal LAMP1 glycosylation may play a role in Niemann-Pick disease, type C pathology

Quantitative, Label‐Free Proteomics in the Symptomatic Niemann–Pick, Type C1 Mouse Model Using Standard Flow Liquid Chromatography and Thermal Focusing Electrospray Ionization

The Lysosome: A Potential Therapeutic Juncture between the COVID-19 Pandemic and Niemann-Pick Type C Disease

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