Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20205018 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5018 ◽

Cited By ~ 9

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.

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

Cholesterol ◽

10.1155/2011/176802 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 45

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21238979 ◽

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.

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

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.647860 ◽

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.

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