scholarly journals npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Malgorzata Wiweger ◽  
Lukasz Majewski ◽  
Dobrochna Adamek-Urbanska ◽  
Iga Wasilewska ◽  
Jacek Kuznicki
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Cell Damage ◽  
Nile Blue ◽  
Premature Death ◽  
Blue Staining ◽  
Small Scale ◽  
Lysosomal Storage ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disease that is caused by a mutation of the NPC1 or NPC2 gene, in which un-esterified cholesterol and sphingolipids accumulate mainly in the liver, spleen, and brain. Abnormal lysosomal storage leads to cell damage, neurological problems, and premature death. The time of onset and severity of symptoms of NPC disease are highly variable. The molecular mechanisms that are responsible for NPC disease pathology are far from being understood. The present study generated and characterized a zebrafish mutant that lacks Npc2 protein that may be useful for studies at the organismal, cellular, and molecular levels and both small-scale and high-throughput screens. Using CRISPR/Cas9 technology, we knocked out the zebrafish homolog of NPC2. Five-day-old npc2 mutants were morphologically indistinguishable from wildtype larvae. We found that live npc2–/– larvae exhibited stronger Nile blue staining. The npc2–/– larvae exhibited low mobility and a high anxiety-related response. These behavioral changes correlated with downregulation of the mcu (mitochondrial calcium uniporter) gene, ppp3ca (calcineurin) gene, and genes that are involved in myelination (mbp and mpz). Histological analysis of adult npc2–/– zebrafish revealed that pathological changes in the nervous system, kidney, liver, and pancreas correlated with inflammatory responses (i.e., the upregulation of il1, nfκβ, and mpeg; i.e., hallmarks of NPC disease). These findings suggest that the npc2 mutant zebrafish may be a model of NPC disease.

scholarly journals Release of acidic store calcium is required for effective priming of the NLRP3 inflammasome

2022 ◽  
Author(s):  
Nick Platt ◽  
Dawn Shepherd ◽  
Yuzhe Weng ◽  
Grant Charles Churchill ◽  
Antony Galione ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Calcium Release ◽  
Inflammatory Responses ◽  
Lysosomal Storage ◽  
Release Channel ◽  
Type C ◽  
Niemann Pick ◽  
Lysosomal Protein

The lysosome is a dynamic signaling organelle that is critical for cell functioning. It is a regulated calcium store that can contribute to Ca2+-regulated processes via both local calcium release and more globally by influencing ER Ca2+release. Here, we provide evidence from studies of an authentic mouse model of the lysosomal storage disease Niemann-Pick Type C (NPC) that has reduced lysosomal Ca2+ levels, and genetically modified mice in which the two-pore lysosomal Ca2+ release channel family are deleted that lysosomal Ca2+ signaling is required for normal pro-inflammatory responses. We demonstrate that production of the pro-inflammatory cytokine IL-1beta via the NLRP3 inflammasome is significantly reduced in murine Niemann-Pick Type C, the inhibition is selective because secretion of TNF alpha is not diminished, and it is a consequence of inefficient inflammasome priming. Synthesis of precursor ProIL-1 beta is significantly reduced in macrophages genetically deficient in the lysosomal protein Npc1, which is mutated in most clinical cases of NPC, and in wild type cells in which Npc1 activity is pharmacologically inhibited. Comparable reductions in ProIL-1 beta generation were measured in vitro and in vivo by macrophages genetically altered to lack expression of the two-pore lysosomal Ca2+ release channels Tpcn1 or Tpcn2. These data demonstrate a requirement for lysosome-dependent Ca2+ signaling in the generation of specific pro-inflammatory responses.

scholarly journals The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field

2021 ◽  
Vol 22 (3) ◽  
pp. 1331
Author(s):  
Daniela Sorriento ◽  
Guido Iaccarino
Keyword(s):  
Fabry Disease ◽  
Molecular Mechanisms ◽  
Cell Damage ◽  
Research Field ◽  
Cardiac Cell ◽  
Lysosomal Storage ◽  
Clinical Level ◽  
New Findings ◽  
Alpha Gene ◽  
Alpha Galactosidase

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD’s development and progression that could become useful targets for therapeutics. This review discusses FD’s cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.

scholarly journals Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1

2009 ◽  
Vol 20 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Michelle S. Steen ◽  
Marvin E. Adams ◽  
Yan Tesch ◽  
Stanley C. Froehner
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Mdx Mouse ◽  
Lysosomal Storage ◽  
Transgenic Expression ◽  
New Therapeutic Approaches ◽  
Human Disorders ◽  
Niemann Pick ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.

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 Vorinostat, a Histone Deacetylase Inhibitor, as a Candidate Therapy to Treat Liver Pathology in a Niemann-Pick type C Disease Mouse Model

2021 ◽  
Author(s):  
◽  
Natalie Hammond
Keyword(s):  
Clinical Trial ◽  
Liver Disease ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Therapeutic Efficacy ◽  
Premature Death ◽  
Unesterified Cholesterol ◽  
Deacetylase Inhibitor ◽  
Type C ◽  
Niemann Pick

<p>Niemann-Pick type C (NPC) disease is a rare neuro-visceral, lysosomal storage disorder for which no effective therapy yet exists. A recessive mutation in the late endosomal/lysosomal cholesterol transport genes NPC1 (95%) or NPC2 (5%) are the causative factors which leads to an accumulation of unesterified cholesterol and sphingolipids in the late endosome/lysosome. It is a build-up of these lipids that, in the majority of cases, ultimately leads to premature death prior to adolescence. In recent years, an imbalance of histone acetylation in a yeast model of NPC disease and subsequently an increased expression of histone deacetylase genes in NPC patient fibroblasts relative to healthy controls was discovered. This led to the finding that Vorinostat (suberoylanilide hydroxamic acid (SAHA); Zolinza®) a histone deacetylase inhibitor (HDACi) drug, rescued unesterified cholesterol accumulation in NPC patient fibroblasts. From these findings in NPC patient fibroblasts, a Phase I clinical trial testing the efficacy of orally-administered Vorinostat in adult NPC disease patients commenced in 2014; however, the therapeutic efficacy of Vorinostat in a whole animal model of NPC disease has not been investigated and is thus unknown. In this thesis, the therapeutic efficacy of intra-peritoneal administered 150 mg/kg Vorinostat in the Npc1nmf164 mouse was explored. This internationally approved HDACi reduced liver disease by decreasing lipid accumulation without increasing expression of NPC1; however, the treatment did not delay weight loss, onset of ataxia and premature death, possibly due to insufficient concentrations penetrating through the blood brain barrier. Transcriptome analysis suggested Vorinostat improved liver disease in a pleiotropic manner, not surprising given the epigenetic nature of HDACi at the gene expression level. Overall, the results herein are of particular importance to the current clinical trial where the therapeutic efficacy is being investigated without any knowledge of efficacy in an animal of NPC disease.</p>

Model construction of Niemann-Pick type C disease in zebrafish

2018 ◽  
Vol 399 (8) ◽  
pp. 903-910 ◽  
Author(s):  
Yusheng Lin ◽  
Xiaolian Cai ◽  
Guiping Wang ◽  
Gang Ouyang ◽  
Hong Cao
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Lipid Profiling ◽  
Zebrafish Model ◽  
Reduced Body ◽  
Significant Difference ◽  
Abnormal Accumulation ◽  
Purkinje Cell Death ◽  
Type C ◽  
Niemann Pick

Abstract Niemann-Pick type C disease (NPC) is a rare human disease, with limited effective treatment options. Most cases of NPC disease are associated with inactivating mutations of the NPC1 gene. However, cellular and molecular mechanisms responsible for the NPC1 pathogenesis remain poorly defined. This is partly due to the lack of a suitable animal model to monitor the disease progression. In this study, we used CRISPR to construct an NPC1−/− zebrafish model, which faithfully reproduced the cardinal pathological features of this disease. In contrast to the wild type (WT), the deletion of NPC1 alone caused significant hepatosplenomegaly, ataxia, Purkinje cell death, increased lipid storage, infertility and reduced body length and life span. Most of the NPC1−/− zebrafish died within the first month post fertilization, while the remaining specimens developed slower than the WT and died before reaching 8 months of age. Filipin-stained hepatocytes of the NPC1−/− zebrafish were clear, indicating abnormal accumulation of unesterified cholesterol. Lipid profiling showed a significant difference between NPC1−/− and WT zebrafish. An obvious accumulation of seven sphingolipids was detected in livers of NPC1−/− zebrafish. In summary, our results provide a valuable model system that could identify promising therapeutic targets and treatments for the NPC 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.

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 &ldquo;unfavorable&rdquo; 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 &ldquo;transient&rdquo; NPC-like lysosomal dysfunction, could hold answers for targeting the ongoing COVID-19 pandemic.

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