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 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.

Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment

US Neurology ◽  
2010 ◽  
Vol 06 (01) ◽  
pp. 88 ◽  
Author(s):  
Cristin D Davidson ◽  
Steven U Walkley ◽  
◽  
Keyword(s):  
Motor Skills ◽  
Therapeutic Option ◽  
Disease Onset ◽  
Cns Involvement ◽  
Progressive Decline ◽  
Inherited Metabolic Disorder ◽  
Intellectual Function ◽  
Lysosomal System ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C (NPC) disease is a rare and fatal inherited metabolic disorder that results in intracellular accumulation of cholesterol and glycolipids within the endosomal/lysosomal system. Central nervous system (CNS) involvement is especially prominent as evidenced by ataxia and progressive decline of motor skills and intellectual function. Defects in either the NPC1 or NPC2 protein, both of which are thought to be involved in the egress of cholesterol and other lipids out of the endosomal/lysosomal system, leads to NPC disease. The pathogenic cascade is not well understood, and currently there is no corrective therapy for NPC patients. However, some compounds tested in animal models of NPC disease have shown promise in slowing disease onset and progression, and administration of these drugs in combination has provided evidence of synergy and enhanced clinical benefit. This favorable outcome indicates that combinatorial therapies using small molecules likely represent the best therapeutic option available to NPC patients at this time.

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 In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease

Nanomaterials ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 802 ◽  
Author(s):  
Yuki Maeda ◽  
Keiichi Motoyama ◽  
Rena Nishiyama ◽  
Taishi Higashi ◽  
Risako Onodera ◽  
...  
Keyword(s):  
Free Cholesterol ◽  
Subcutaneous Administration ◽  
Safety Evaluation ◽  
Autosomal Recessive Disorder ◽  
Liver Cells ◽  
High Dose ◽  
Efficacy And Safety ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C disease (NPC) is a fatal, autosomal recessive disorder, which causes excessive accumulation of free cholesterol in endolysosomes, resulting in progressive hepatomegaly and neurodegeneration. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used at a high dose for the treatment of NPC, risking lung toxicity and hearing loss during treatment. One method to reduce the required dose of HP-β-CyD for the treatment of hepatomegaly is to actively deliver β-cyclodextrin (β-CyD) to hepatocytes. Previously, we synthesized lactosyl-β-CyD (Lac-β-CyD) and demonstrated that it lowers cholesterol in NPC model liver cells. In the present study, we studied the efficacy and safety of Lac-β-CyD treatment of hepatomegaly in Npc1−/− mice. After subcutaneous administration, Lac-β-CyD accumulated in the liver and reduced hepatomegaly with greater efficacy than HP-β-CyD. In addition, subcutaneous administration of a very high dose of Lac-β-CyD was less toxic to the lungs than HP-β-CyD. Notably, the accumulation of intracellular free cholesterol in endolysosomes of NPC-like liver cells was significantly lower after administration of Lac-β-CyD than after treatment with HP-β-CyD. In conclusion, these results suggest that Lac-β-CyD is a candidate for the effective treatment of hepatomegaly in NPC.

scholarly journals Niemann-Pick disease type C: a case series of Brazilian patients

2014 ◽  
Vol 72 (3) ◽  
pp. 214-218 ◽  
Author(s):  
Paulo José Lorenzoni ◽  
Elaine Cardoso ◽  
Ana C. S. Crippa ◽  
Charles Marques Lourenço ◽  
Fernanda Timm Seabra Souza ◽  
...  
Keyword(s):  
Treatment Response ◽  
Laboratory Data ◽  
Disease Onset ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Npc1 Gene ◽  
Variant Pattern ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the “variant” pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis.

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 Neurodegeneration in Niemann–Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment

2021 ◽  
Vol 22 (12) ◽  
pp. 6600
Author(s):  
Ida Cariati ◽  
Laura Masuelli ◽  
Roberto Bei ◽  
Virginia Tancredi ◽  
Claudio Frank ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Physical Exercise ◽  
Cortical Neurons ◽  
Current Knowledge ◽  
Neurofibrillary Tangle ◽  
Lysosomal System ◽  
Type C ◽  
Niemann Pick ◽  
Molecular And Biochemical Mechanisms

Niemann–Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease.

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 Niemann–Pick disease type C in Palestine: genotype and phenotype of sixteen patients and report of a novel mutation in the NPC1 gene

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Imad Dweikat ◽  
Othman Thaher ◽  
Abdulrahman Abosleem ◽  
Almotazbellah Zeer ◽  
Ameer Abo Mokh
Keyword(s):  
Novel Mutation ◽  
Tertiary Care ◽  
Disease Onset ◽  
Disease Type ◽  
Cerebellar Hemisphere ◽  
Niemann Pick Disease ◽  
Npc1 Gene ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

Abstract Background Niemann–Pick disease type C (NPC) is an autosomal recessive, neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in these genes are associated with abnormal endosomal–lysosomal trafficking, resulting in the accumulation of tissue-specific lipids in lysosomes. Methods We described sixteen patients with NPC diagnosed between the age of 1 month and 30 years at two tertiary care centers in Palestine. The clinical phenotype, brain magnetic resonance imaging (MRI), and molecular genetic analysis data were reviewed. Results The diagnosis was confirmed by molecular analysis in all patients. Fourteen out of sixteen patients were homozygous for the NPC1 p.G992W variant. Among them, most were categorized as having the late-infantile neurological form of disease onset. They predominantly manifested with early-onset visceral manifestations in the form of hepatosplenomegaly and prolonged neonatal jaundice, and late-onset neuropsychiatric manifestations in the form of vertical supranuclear gaze palsy (VSGP), ataxia, cognitive impairment and seizures. Brain MRI in 6 patients was normal in 5 or consistent with cerebellar hemisphere atrophy in 1 of them. Two other mutations were identified in the NPC1 gene, of which p.V845Cfs*24 was novel. Conclusions Our results revealed phenotypic heterogeneity of NPC even within the same genotype, and add to the increasingly recognized evidence that cholestatic jaundice and hepatosplenomegaly during infancy, should alert the physician for the possibility of NPC. We reported a novel mutation in the NPC1 gene further expanding its genotype.

Sign in / Sign up

Export Citation Format

Share Document