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 Effects of curcumin nanoformulations on cellular function in Niemann-Pick disease type C astrocytes

2017 ◽  
Author(s):  
Emily Maguire ◽  
Luke J. Haslett ◽  
Joanne L. Welton ◽  
Helen Waller-Evans ◽  
Jule Goike ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Disease Type ◽  
Lipid Storage ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
And Function ◽  
Pick Disease

AbstractNiemann-Pick disease type C1 (NPC disease) is a neurodegenerative multi-lipid lysosomal storage disease caused by mutations in the NPC1 gene presenting with reduced lysosomal Ca2+ signalling and inhibited late endosome-lysosome transport. Elevating cytosolic Ca2+ levels in NPC cells has been shown to reduce lysosomal lipid storage. Treating Npc1-/- mice with the Ca2+ modulator curcumin led to reduced lipid storage, improved life expectancy and function. These studies led to reported utilisation of curcumin supplements by NPC disease families despite there being no clinical evidence of benefit and a report indicating no benefit of nanoformulated curcumin in Npc1-/- mice. The aim of this study was to determine whether various commercially available curcumin nanoformulations were capable of reproducing the findings obtained with unformulated pharmaceutical grade curcumin. We compared seven curcumin nanoformulations in Npc1-/- mouse astrocytes. All the nanoformulations elevate cytosolic Ca2+ levels but only two lowered lysosomal lipid storage. Importantly, some caused elevations in NPC lysosomal storage and/or decreased cellular viability. Although this is an in vitro study, our findings suggest that care should be taken when contemplating the use of curcumin supplements for NPC disease.

A lysosomal storage disorder in mice: A model of Niemann-Pick disease

1982 ◽  
Vol 5 (4) ◽  
pp. 239-240 ◽  
Author(s):  
T. Sakiyama ◽  
M. Tsuda ◽  
T. Kitagawa ◽  
R. Fujita ◽  
S. Miyawaki
Keyword(s):  
Lysosomal Storage Disorder ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Storage Disorder ◽  
Niemann Pick ◽  
Pick Disease

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 In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C

2019 ◽  
Vol 20 (5) ◽  
pp. 1152 ◽  
Author(s):  
Nushrat Yasmin ◽  
Yoichi Ishitsuka ◽  
Madoka Fukaura ◽  
Yusei Yamada ◽  
Shuichi Nakahara ◽  
...  
Keyword(s):  
Free Cholesterol ◽  
Disease Type ◽  
Cholesterol Trafficking ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Deficient Mice ◽  
Pick Disease

Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-β-cyclodextrin (G2-β-CD) as a drug candidate against NPC. The physicochemical properties of G2-β-CD as an injectable agent were assessed, and molecular interactions between G2-β-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-β-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-β-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-β-CD formed higher-order inclusion complexes with free cholesterol. G2-β-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-β-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-β-CD (21.4 μmol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-β-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models.

scholarly journals Effect of Maltosyl-Beta-cyclodextrin on in vitro and in vivo models of Niemann-Pick disease type C

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO3-8-13
Author(s):  
Nushrat Yasmin ◽  
Yoichi Ishitsuka ◽  
Yusei Yamada ◽  
Madoka Fukaura ◽  
Shuichi Nakahara ◽  
...  
Keyword(s):  
Disease Type ◽  
In Vivo Models ◽  
Beta Cyclodextrin ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

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

2017 ◽  
Vol 2 ◽  
pp. 76 ◽  
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.

Niemann-Pick Disease Type C with Isolated Splenomegaly: A Case Report in a Child

2021 ◽  
Author(s):  
Bruna Ribeiro Torres ◽  
Daniela Otoni Russo ◽  
Vinícius Andrade Gomes Vuolo ◽  
Tarcísio Silva Borborema ◽  
André Vinícius Soares Barbosa ◽  
...  
Keyword(s):  
Autosomal Recessive Inheritance ◽  
Signs And Symptoms ◽  
Disease Type ◽  
Sphingolipid Metabolism ◽  
Neurological Involvement ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

AbstractNiemann-Pick disease type C is an innate error of lysosomal storage metabolism with an autosomal recessive inheritance pattern. The disease causes intracellular cholesterol accumulation and changes in sphingolipid metabolism. If cholesterol accumulates, the signs and symptoms of visceral involvement predominate. Neurological involvement results from sphingolipid accumulation. A 7-year-old student was referred to a tertiary service for the investigation of asymptomatic splenomegaly. Following an extensive examination, he was diagnosed with Niemann-Pick disease type C. Interestingly, this case's only symptom was splenomegaly.

scholarly journals Generation of patient specific human neural stem cells from Niemann-Pick disease type C patient-derived fibroblasts

Oncotarget ◽  
2017 ◽  
Vol 8 (49) ◽  
pp. 85428-85441 ◽  
Author(s):  
Eun-Ah Sung ◽  
Kyung-Rok Yu ◽  
Ji-Hee Shin ◽  
Yoojin Seo ◽  
Hyung-Sik Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Disease Type ◽  
Patient Specific ◽  
Human Neural Stem Cells ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease
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