Free sphingoid bases in tissues from patients with type C Niemann-Pick disease and other lysosomal storage disorders

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.

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Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

F1000Research ◽

10.12688/f1000research.12361.1 ◽

2018 ◽

Vol 7 ◽

pp. 194 ◽

Cited By ~ 5

Author(s):

Alberto Benussi ◽

Maria Sofia Cotelli ◽

Alessandro Padovani ◽

Barbara Borroni

Keyword(s):

Response To Treatment ◽

The European Union ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Disease Staging ◽

Type C ◽

Niemann Pick ◽

New Treatments ◽

Pick Disease ◽

Disease Pathways

Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer’s disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults. A number of ongoing clinical trials might hold promise for the development of new treatments for NPC. The objective of the present work is to review and evaluate recent literature data in order to highlight the latest neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC pathophysiology. Furthermore, ongoing developments in disease-modifying treatments will be briefly discussed.

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Studies on a sphingolipid activator protein ( SAP-2) in fibroblasts from patients with lysosomal storage diseases, including Niemann-Pick disease Type C

Clinica Chimica Acta ◽

10.1016/0009-8981(85)90053-1 ◽

1985 ◽

Vol 146 (2-3) ◽

pp. 147-156 ◽

Cited By ~ 19

Author(s):

Shinsuke Fujibayashi ◽

David A. Wenger

Keyword(s):

Lysosomal Storage Diseases ◽

Disease Type ◽

Lysosomal Storage ◽

Storage Diseases ◽

Activator Protein ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2020.165875 ◽

2020 ◽

Vol 1866 (10) ◽

pp. 165875

Author(s):

M.J. Yañez ◽

T. Marín ◽

E. Balboa ◽

A.D. Klein ◽

A.R. Alvarez ◽

...

Keyword(s):

Lysosomal Storage Disorders ◽

Therapeutic Interventions ◽

Lysosomal Storage ◽

Type C ◽

Niemann Pick ◽

Storage Disorders

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

Behavioural Brain Research ◽

10.1016/j.bbr.2015.10.021 ◽

2016 ◽

Vol 297 ◽

pp. 213-223 ◽

Cited By ~ 6

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

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Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders

10.1101/267948 ◽

2018 ◽

Author(s):

Jarmila Králová ◽

Michal Jurášek ◽

Lucie Krčová ◽

Bohumil Dolenský ◽

Ivan Novotný ◽

...

Keyword(s):

Genetic Mutation ◽

Lysosomal Storage Disorders ◽

Cholesterol Homeostasis ◽

Fluorescence Labeling ◽

Lysosomal Storage ◽

Animal Cells ◽

Design And Synthesis ◽

Niemann Pick Disease ◽

Niemann Pick ◽

Storage Disorders

AbstractThe monitoring of intracellular cholesterol homeostasis and trafficking is of great importance because their imbalance leads to many pathologies. Reliable tools for cholesterol detection are in demand. This study presents the design and synthesis of fluorescent probes for cholesterol recognition and demonstrates their selectivity by a variety of methods. The construction of dedicated library of 14 probes was based on heterocyclic (pyridine)-sterol derivatives with various attached fluorophores. The most promising probe, a P1-BODIPY conjugate FP-5, was analyzed in detail and showed an intensive labeling of cellular membranes followed by intracellular redistribution into various cholesterol rich organelles and vesicles. FP-5 displayed a stronger signal, with faster kinetics, than the commercial TF-Chol probe. In addition, cells with pharmacologically disrupted cholesterol transport, or with a genetic mutation of cholesterol transporting protein NPC1, exhibited strong and fast FP-5 labeling in the endo/lysosomal compartment, co-localizing with filipin staining of cholesterol. Hence, FP-5 has high potential as a new probe for monitoring cholesterol trafficking and its disorders.Significance statementCholesterol is a vital steroid molecule with many important functions in animal cells. Although its dysregulation is associated with an expanding list of clinically important pathologies, the study of its role is limited by a lack of reliable tools for live intracellular monitoring. This study demonstrates the applicability of a novel class of heterocyclic sterol probes. These probes exhibit fast cellular uptake with effective fluorescence labeling of sterol species in a variety of living cells, without a need for artificial carriers. When applied to Niemann-Pick disease type C1 cells, they identified massive accumulation of cholesterol in the endosome/lysosome compartment. Thus, several probes from the same series can also be used for visualizing lysosomal storage disorders and sterol transporting pathologies.

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Biomarkers for Lysosomal Storage Disorders with an Emphasis on Mass Spectrometry

International Journal of Molecular Sciences ◽

10.3390/ijms21082704 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2704 ◽

Cited By ~ 2

Author(s):

Ryuichi Mashima ◽

Torayuki Okuyama ◽

Mari Ohira

Keyword(s):

Mass Spectrometry ◽

Biomarker Discovery ◽

Short Review ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Clinical Diagnoses ◽

History Of ◽

Niemann Pick ◽

Storage Disorders

Lysosomal storage disorders (LSDs) are characterized by an accumulation of various substances, such as sphingolipids, mucopolysaccharides, and oligosaccharides. The LSD enzymes responsible for the catabolism are active at acidic pH in the lysosomal compartment. In addition to the classically established lysosomal degradation biochemistry, recent data have suggested that lysosome plays a key role in the autophagy where the fusion of autophagosome and lysosome facilitates the degradation of amino acids. A failure in the lysosomal function leads to a variety of manifestations, including neurovisceral disorders. While affected individuals appear to be normal at birth, they gradually become symptomatic in childhood. Biomarkers for each condition have been well-documented and their proper selection helps to perform accurate clinical diagnoses. Based on the natural history of disorders, it is now evident that the existing treatment becomes most effective when initiated during presymptomatic period. Neonatal screening provides such a platform for inborn error of metabolism in general and is now expanding to LSDs as well. These are implemented in some areas and countries, including Taiwan and the U.S. In this short review, we will discuss several issues on some selected biomarkers for LSDs involving Fabry, Niemann–Pick disease type C, mucopolysaccharidosis, and oligosaccharidosis, with a focus on mass spectrometry application to biomarker discovery and detection.

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Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

Wellcome Open Research ◽

10.12688/wellcomeopenres.12431.1 ◽

2017 ◽

Vol 2 ◽

pp. 76 ◽

Cited By ~ 1

Author(s):

Elena-Raluca Nicoli ◽

David Smith ◽

Lauren Morris ◽

Frances M. Platt

Keyword(s):

Bile Acid ◽

Mouse Model ◽

Acid Treatment ◽

Disease Type ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Cholanic Acid ◽

Pick Disease

Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and in post-mortem liver from NPC patients. As bile acids regulate the P450 system, we tested bile acid treatment using ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, which is used to treat several cholestatic disorders. In this study, we compared UDCA treatment with the bile acid cholic acid (CA), and found unexpected hepatotoxicity in response to CA in Npc1 mice, but not to UDCA, suggesting that only UDCA should be used as an adjunctive therapy in NPC patients.

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