scholarly journals Complement Component C3 Participates in Early Stages of Niemann–Pick C Mouse Liver Damage

2020 ◽  
Vol 21 (6) ◽  
pp. 2127 ◽  
Author(s):  
Andrés D. Klein ◽  
Javier González de la Vega ◽  
Silvana Zanlungo
Keyword(s):  
Liver Damage ◽  
Complement Cascade ◽  
Lysosomal Storage ◽  
Positive Effects ◽  
Early Stages ◽  
Complement Component C3 ◽  
Npc1 Gene ◽  
Type C ◽  
Niemann Pick ◽  
Short Time

Niemann–Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann–Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the innate immunity response, recognizes danger signals from injured tissues. We aimed to determine whether there is activation of the complement system in the liver of the NPC mouse and to assess the relationship between C3 activation, a final component of the pathway, and NPC liver pathology. Niemann–Pick type C mice showed high levels of C3 staining in the liver which unexpectedly decreased with aging. Using an inducible NPC1 hepatocyte rescue mouse model, we restored NPC1 expression for a short time in young mice. We found C3 positive cells only in non-rescued cells, suggesting that C3 activation in NPC cells is reversible. Then, we studied the effect of C3 ablation on NPC liver damage at two postnatal time points, P56 and P72. Deletion of C3 reduced the presence of hepatic CD68-positive cells at postnatal day 56 and prevented the increase of transaminase levels in the blood of NPC mice. These positive effects were abrogated at P72, indicating that the complement cascade participates only during the early stages of liver damage in NPC mice, and that its inhibition may serve as a new potential therapeutic strategy for the disease.

scholarly journals Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2159
Author(s):  
Elisa Balboa ◽  
Tamara Marín ◽  
Juan Esteban Oyarzún ◽  
Pablo S. Contreras ◽  
Robert Hardt ◽  
...  
Keyword(s):  
Liver Damage ◽  
Therapeutic Targets ◽  
Bioinformatic Analysis ◽  
P Value ◽  
Lysosomal Storage ◽  
Npc1 Gene ◽  
The Central Nervous System ◽  
Type C ◽  
Niemann Pick ◽  
Lysosomal Proteins

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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.

Possible genotype-phenotype correlations in Niemann-Pick type C patients and miglustat treatment

2021 ◽  
Vol 74 (3-4) ◽  
pp. 139-144
Author(s):  
Nafiye Emel Çakar ◽  
Hasan Önal
Keyword(s):  
Motor Development ◽  
Clinical Laboratory ◽  
Homozygous Mutation ◽  
Lung Involvement ◽  
Lysosomal Storage ◽  
Npc1 Gene ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene ◽  
Severe Lung

Niemann-Pick type C is a rare lysosomal storage disease caused by impaired intracellular cholesterol transport. The autosomal recessive disease is caused by mutations in NPC1 or NPC2 genes. Clinical-laboratory features, genotype-phenotype correlation and miglustat treatment response of our patients diagnosed with early infantile Niemann-Pick type C were evaluated. In this article, four Niemann-Pick type C patients diagnosed in the early infantile period are presented. Common features of our patients were hepatomegaly, splenomegaly, cholestasis and retardation in motor development. Patients 1 and 2 are twins, with homozygous mutation c.2776G>A p.(Ala926Thr) in NPC1 gene and severe lung involvement. Lung involvement, which is mostly associated with NPC2 gene mutation in the literature, was severe in our patients and they died early. In patients 3 and 4, there were respectively c.2972del p.(Gln991Argfs*6) mutation in NPC1 gene and c.133C>T p.(Gln45*) homozygous mutation in NPC2 gene. In these two patients, improvement in neurological findings were observed with treatment of miglustat. In our twin patients, severe lung involvement was observed. Two of our four early infantile Niemann-Pick type C patients exhibited neurological gains with miglustat treatment.

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

Novel compound heterozygous mutation in NPC1 gene cause Niemann–Pick disease type C with juvenile onset

2020 ◽  
Vol 99 (1) ◽  
Author(s):  
Maria Cristina Costanzo ◽  
Antonio Gennaro Nicotera ◽  
Mirella Vinci ◽  
Aurelio Vitello ◽  
Agata Fiumara ◽  
...  
Keyword(s):  
Disease Type ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Juvenile Onset ◽  
Niemann Pick Disease ◽  
Npc1 Gene ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

scholarly journals Hearing Loss is an Early Consequence of Npc1 Gene Deletion in the Mouse Model of Niemann–Pick Disease, Type C

2014 ◽  
Vol 15 (4) ◽  
pp. 529-541 ◽  
Author(s):  
Kelly A. King ◽  
Sandra Gordon-Salant ◽  
Karen S. Pawlowski ◽  
Anna M. Taylor ◽  
Andrew J. Griffith ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mouse Model ◽  
Gene Deletion ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Npc1 Gene ◽  
Type C ◽  
Niemann Pick ◽  
Pick 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 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 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.

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