scholarly journals Lyso-glycosphingolipids: presence and consequences

2020 ◽  
Vol 64 (3) ◽  
pp. 565-578 ◽  
Author(s):  
Marco van Eijk ◽  
Maria J. Ferraz ◽  
Rolf G. Boot ◽  
Johannes M.F.G. Aerts
Keyword(s):  
Metachromatic Leukodystrophy ◽  
Lysosomal Storage Diseases ◽  
Krabbe Disease ◽  
Lysosomal Storage ◽  
Gm2 Gangliosidosis ◽  
Acid Ceramidase ◽  
Lysosomal Diseases ◽  
Type C ◽  
Niemann Pick ◽  
Storage Disorders

Abstract Lyso-glycosphingolipids are generated in excess in glycosphingolipid storage disorders. In the course of these pathologies glycosylated sphingolipid species accumulate within lysosomes due to flaws in the respective lipid degrading machinery. Deacylation of accumulating glycosphingolipids drives the formation of lyso-glycosphingolipids. In lysosomal storage diseases such as Gaucher Disease, Fabry Disease, Krabbe disease, GM1 -and GM2 gangliosidosis, Niemann Pick type C and Metachromatic leukodystrophy massive intra-lysosomal glycosphingolipid accumulation occurs. The lysosomal enzyme acid ceramidase generates the deacylated lyso-glycosphingolipid species. This review discusses how the various lyso-glycosphingolipids are synthesized, how they may contribute to abnormal immunity in glycosphingolipid storing lysosomal diseases and what therapeutic opportunities exist.

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

2020 ◽  
Author(s):  
Rami Ballout
Keyword(s):  
Mechanisms Of Action ◽  
Comparable Efficacy ◽  
Lysosomal Storage ◽  
Viral Propagation ◽  
Lysosomal Dysfunction ◽  
The World ◽  
The Face ◽  
Type C ◽  
Niemann Pick ◽  
Storage Disorders

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.

scholarly journals Circadian profiling in two mouse models of lysosomal storage disorders; Niemann Pick type-C and Sandhoff disease

2016 ◽  
Vol 297 ◽  
pp. 213-223 ◽  
Author(s):  
Katie Richardson ◽  
Achilleas Livieratos ◽  
Richard Dumbill ◽  
Steven Hughes ◽  
Gauri Ang ◽  
...  
Keyword(s):  
Mouse Models ◽  
Sandhoff Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Type C ◽  
Niemann Pick ◽  
Storage Disorders

scholarly journals Gene therapy: prospects for glycolipid storage diseases

2003 ◽  
Vol 358 (1433) ◽  
pp. 921-925 ◽  
Author(s):  
Volkmar Gieselmann ◽  
Ulrich Matzner ◽  
Diana Klein ◽  
Jan Eric Mansson ◽  
Rudi D'Hooge ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Models ◽  
Metachromatic Leukodystrophy ◽  
Lysosomal Storage Diseases ◽  
Degradation Pathway ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Lysosomal Disorders ◽  
Lysosomal Diseases

Lysosomal storage diseases comprise a group of about 40 disorders, which in most cases are due to the deficiency of a lysosomal enzyme. Since lysosomal enzymes are involved in the degradation of various compounds, the diseases can be further subdivided according to which pathway is affected. Thus, enzyme deficiencies in the degradation pathway of glycosaminoglycans cause mucopolysaccharidosis, and deficiencies affecting glycopeptides cause glycoproteinosis. In glycolipid storage diseases enzymes are deficient that are involved in the degradation of sphingolipids. Mouse models are available for most of these diseases, and some of these mouse models have been used to study the applicability of in vivo gene therapy. We review the rationale for gene therapy in lysosomal disorders and present data, in particular, about trials in an animal model of metachromatic leukodystrophy. The data of these trials are compared with those obtained with animal models of other lysosomal diseases.

scholarly journals Treatment trials in Niemann-Pick type C disease

2021 ◽  
Author(s):  
Dominika Sitarska ◽  
Anna Tylki-Szymańska ◽  
Agnieszka Ługowska
Keyword(s):  
Animal Studies ◽  
Autosomal Recessive ◽  
Lysosomal Storage Diseases ◽  
Cholesterol Transport ◽  
Inherited Disease ◽  
Lysosomal Storage ◽  
Late Endosomes ◽  
Type C ◽  
Niemann Pick ◽  
Genetically Determined

AbstractNiemann-Pick type C (NPC) disease is a genetically determined neurodegenerative metabolic disease. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. It is an autosomal recessive inherited disease that results from mutations in the NPC1 or NPC2 genes. The treatment efforts are focused on the slowing its progression. The only registered drug, devoted for NPC patients is Miglustat. Effective treatment is still under development. NPC disease mainly affects the nervous system, and the crossing of the blood–brain barrier by medicines is still a challenge, therefore the combination therapies of several compounds are increasingly being worked on. The aim of this paper is to present the possibilities in treatment of Niemann-Pick type C disease. The discussed research results relate to animal studies.

scholarly journals Metabolomic Studies of Lipid Storage Disorders, with Special Reference to Niemann-Pick Type C Disease: A Critical Review with Future Perspectives

2020 ◽  
Vol 21 (7) ◽  
pp. 2533 ◽  
Author(s):  
Benita Claire Percival ◽  
Miles Gibson ◽  
Philippe B. Wilson ◽  
Frances M. Platt ◽  
Martin Grootveld
Keyword(s):  
State Of The Art ◽  
Lysosomal Storage ◽  
Future Perspectives ◽  
Cell Dysfunction ◽  
Large Numbers ◽  
The Central Nervous System ◽  
Type C ◽  
Niemann Pick ◽  
Bioanalytical Techniques ◽  
Storage Disorders

Lysosomal storage disorders (LSDs) are predominantly very rare recessive autosomal neurodegenerative diseases.Sphingolipidoses, a sub-group of LSDs, result from defects in lysosomal enzymes involved in sphingolipid catabolism, and feature disrupted storage systems which trigger complex pathogenic cascades with other organelles collaterally affected. This process leads to cell dysfunction and death, particularly in the central nervous system. One valuable approach to gaining insights into the global impact of lysosomal dysfunction is through metabolomics, which represents a discovery tool for investigating disease-induced modifications in the patterns of large numbers of simultaneously-analysed metabolites, which also features the identification of biomarkers Here, the scope and applications of metabolomics strategies to the investigation of sphingolipidoses is explored in order to facilitate our understanding of the biomolecular basis of these conditions. This review therefore surveys the benefits of applying ’state-of-the-art’ metabolomics strategies, both univariate and multivariate, to sphingolipidoses, particularly Niemann-Pick type C disease. Relevant limitations of these techniques are also discussed, along with the latest advances and developments. We conclude that metabolomics strategies are highly valuable, distinctive bioanalytical techniques for probing LSDs, most especially for the detection and validation of potential biomarkers. They also show much promise for monitoring disease progression and the evaluation of therapeutic strategies and targets.

scholarly journals GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice

2021 ◽  
Vol 22 (5) ◽  
pp. 2532
Author(s):  
Martijn J. C. van der Lienden ◽  
Jan Aten ◽  
André R. A. Marques ◽  
Ingeborg S. E. Waas ◽  
Per W. B. Larsen ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Integral Membrane Protein ◽  
Efflux Transporter ◽  
Lysosomal Storage ◽  
Acid Ceramidase ◽  
Galectin 3 ◽  
Lysosomal Accumulation ◽  
Type C ◽  
Niemann Pick ◽  
Membrane Protein Type

The lysosomal storage disease Niemann–Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old Npc1−/− mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In Npc1−/− liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in Npc1−/− liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the Npc1−/− liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in Npc1−/− hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes.

scholarly journals Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C

2012 ◽  
Vol 42 (7) ◽  
pp. 1886-1892 ◽  
Author(s):  
Anneliese O. Speak ◽  
Nicholas Platt ◽  
Mariolina Salio ◽  
Danielle te Vruchte ◽  
David A. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer T Cells ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Killer T Cells ◽  
Invariant Natural Killer ◽  
Pick Disease
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