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 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 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 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

scholarly journals Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann–Pick disease type C

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Seung-Eun Lee ◽  
Nari Shin ◽  
Myung Geun Kook ◽  
Dasom Kong ◽  
Nam Gyo Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lysosomal Storage Disorder ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Storage Disorder ◽  
Niemann Pick ◽  
Pick Disease

AbstractRecent studies on developing three-dimensional (3D) brain organoids from stem cells have allowed the generation of in vitro models of neural disease and have enabled the screening of drugs because these organoids mimic the complexity of neural tissue. Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 or NPC2. The pathological features underlying NPC are characterized by the abnormal accumulation of cholesterol in acidic compartments, including late endosomes and lysosomes. Due to the inaccessibility of brain tissues from human NPC patients, we developed NPC brain organoids with induced neural stem cells from NPC patient-derived fibroblasts. NPC organoids exhibit significantly reduced size and proliferative ability, which are accompanied by accumulation of cholesterol, impairment in neuronal differentiation, and autophagic flux and dysfunction of lysosomes; therefore, NPC organoids can recapitulate the main phenotypes of NPC patients. Furthermore, these pathological phenotypes observed in NPC organoids were reversed by treatment with valproic acid and HPBCD, which are known to be an effective treatment for several neurodegenerative diseases. Our data present patient-specific phenotypes in 3D organoid-based models of NPC and highlight the application of this model to drug screening in vitro.

scholarly journals Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases

2017 ◽  
Vol 2 ◽  
pp. 75 ◽  
Author(s):  
William R.H. Evans ◽  
Elena-Raluca Nicoli ◽  
Raymond Y. Wang ◽  
Nina Movsesyan ◽  
Frances M. Platt
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Liver Enzyme ◽  
Liver Dysfunction ◽  
Case Series ◽  
Later Life ◽  
Lysosomal Storage ◽  
Elevated Liver Enzymes ◽  
Type C ◽  
Niemann Pick

In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters.

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