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 Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emmanuelle Flatt ◽  
Valérie A. McLin ◽  
Olivier Braissant ◽  
Katarzyna Pierzchala ◽  
Paola Mastromarino ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Brain Metabolism ◽  
Treatment Options ◽  
Multimodal Approach ◽  
Ultra High Field ◽  
Neuropsychiatric Disease ◽  
Important Challenge ◽  
Type C ◽  
The Brain

AbstractType C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.

Niemann-Pick Type C Disease - Report on Results from the Niemann-Pick Type C Patient and Healthcare Professional Survey

2011 ◽  
Vol 6 (1) ◽  
pp. 12
Author(s):  
Hans H Klünemann ◽  
J Edmond Wraith ◽  
Frits A Wijburg ◽  
◽  
◽  
...  
Keyword(s):  
Healthcare Professional ◽  
Specific Treatment ◽  
The Body ◽  
Neurological Symptoms ◽  
Diagnostic Process ◽  
Abnormal Accumulation ◽  
Recent Developments ◽  
Type C ◽  
Niemann Pick ◽  
Disease Specific

Niemann-Pick type C disease (NPC) is a rare and progressive genetic condition that is associated with an abnormal accumulation of lysosomal lipids in the body, which manifests as a variety of neurological symptoms that range greatly in severity. Management focuses largely on treating symptoms, but recent developments have led to disease-specific therapy that can slow or stabilise the progression of neurological symptoms in some patients. The Niemann-Pick type C Patient and Healthcare Professional Survey conducted interviews with parents and carers of patients with NPC and with healthcare professionals to identify areas of NPC diagnosis, management and support that need improvement. Specifically, an emphasis was placed on increased awareness of the disease and disease symptoms with enhanced communication between doctors, their colleagues and parents of patients in order to facilitate the diagnostic process and the hope for earlier diagnoses, thereby enabling access to disease-specific treatment. The survey identified a need among families of patients with NPC for more support from doctors in the provision of information about the disease and about locally based social and psychological support, and for support from healthcare organisations that should coordinate all the available services. Such co-ordination could ensure that consistent support is provided for all aspects of patient care and for patients’ families and carers.

scholarly journals Structural Determination of Lysosphingomyelin-509 and Discovery of Novel Class Lipids from Patients with Niemann–Pick Disease Type C

2019 ◽  
Vol 20 (20) ◽  
pp. 5018 ◽  
Author(s):  
Maekawa ◽  
Jinnoh ◽  
Matsumoto ◽  
Narita ◽  
Mashima ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hydrogen Abstraction ◽  
Autosomal Recessive Disorder ◽  
Good Prognosis ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

: Niemann–Pick disease type C (NPC) is an autosomal recessive disorder caused by the mutation of cholesterol-transporting proteins. In addition, early treatment is important for good prognosis of this disease because of the progressive neurodegeneration. However, the diagnosis of this disease is difficult due to a variety of clinical spectrum. Lysosphingomyelin-509, which is one of the most useful biomarkers for NPC, was applied for the rapid and easy detection of NPC. The fact that its chemical structure was unknown until recently implicates the unrevealed pathophysiology and molecular mechanisms of NPC. In this study, we aimed to elucidate the structure of lysosphingomyelin-509 by various mass spectrometric techniques. As our identification strategy, we adopted analytical and organic chemistry approaches to the serum of patients with NPC. Chemical derivatization and hydrogen abstraction dissociation–tandem mass spectrometry were used for the determination of function groups and partial structure, respectively. As a result, we revealed the exact structure of lysosphingomyelin-509 as N-acylated and O-phosphocholine adducted serine. Additionally, we found that a group of metabolites with N-acyl groups were increased considerably in the serum/plasma of patients with NPC as compared to that of other groups using targeted lipidomics analysis. Our techniques were useful for the identification of lysosphingomyelin-509.

scholarly journals The Fruit Fly Drosophila melanogaster as a Model System to Study Cholesterol Metabolism and Homeostasis

Cholesterol ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Ryusuke Niwa ◽  
Yuko S. Niwa
Keyword(s):  
Drosophila Melanogaster ◽  
Steroid Hormones ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Fruit Fly ◽  
Model System ◽  
Biophysical Properties ◽  
Type C ◽  
Niemann Pick

Cholesterol has long been recognized for its versatile roles in influencing the biophysical properties of cell membranes and for serving as a precursor of steroid hormones. While many aspects of cholesterol biosynthesis are well understood, little is currently known about the molecular mechanisms of cholesterol metabolism and homeostasis. Recently, genetic approaches in the fruit fly, Drosophila melanogaster, have been successfully used for the analysis of molecular mechanisms that regulate cholesterol metabolism and homeostasis. This paper summarizes the recent studies on genes that regulate cholesterol metabolism and homeostasis, including neverland, Niemann Pick type C(NPC) disease genes, and DHR96.

scholarly journals Abnormal accumulation and recycling of glycoproteins visualized in Niemann-Pick type C cells using the chemical reporter strategy

2013 ◽  
Vol 110 (25) ◽  
pp. 10207-10212 ◽  
Author(s):  
N. E. Mbua ◽  
H. Flanagan-Steet ◽  
S. Johnson ◽  
M. A. Wolfert ◽  
G.-J. Boons ◽  
...  
Keyword(s):  
C Cells ◽  
Abnormal Accumulation ◽  
Chemical Reporter ◽  
Type C ◽  
Niemann Pick

scholarly journals Understanding and Treating Niemann–Pick Type C Disease: Models Matter

2020 ◽  
Vol 21 (23) ◽  
pp. 8979
Author(s):  
Valentina Pallottini ◽  
Frank W. Pfrieger
Keyword(s):  
Molecular Mechanisms ◽  
Disease Onset ◽  
Autosomal Recessive Disorder ◽  
Experimental Models ◽  
Limiting Factors ◽  
Curative Therapy ◽  
Lysosomal System ◽  
Type C ◽  
Niemann Pick ◽  
General Aspects

Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann–Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal–lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics.

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 Repurposing of Miglustat to inhibit the coronavirus Severe Acquired Respiratory Syndrome SARS-CoV-2

2020 ◽  
Author(s):  
Sreejith Rajasekharan ◽  
Rafaela Milan Bonotto ◽  
Yvette Kazungu ◽  
Lais Nascimento Alves ◽  
Monica Poggianella ◽  
...  
Keyword(s):  
Marked Decrease ◽  
Treatment Options ◽  
Drug Repurposing ◽  
Lysosomal Storage ◽  
Entry Level ◽  
Early Stages ◽  
Oligosaccharide Processing ◽  
Type C ◽  
Post Entry ◽  
Niemann Pick

AbstractRepurposing clinically available drugs to treat the new coronavirus disease COVID-19 is an urgent need in these early stages of the SARS-CoV-2 pandemic, when very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated for SARS-CoV-2 at concentrations achievable in the plasma by current clinical regimens without cytotoxicity. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious virus. The mechanism resides in the inhibitory activity towards α-glucosidases that are involved in early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. The wealth of available data on the clinical use of Miglustat for the treatment of lysosomal storage disorders and the antiviral properties against SARS-CoV-2 make it an ideal candidate for drug repurposing.

Sign in / Sign up

Export Citation Format

Share Document