scholarly journals Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 194 ◽  
Author(s):  
Alberto Benussi ◽  
Maria Sofia Cotelli ◽  
Alessandro Padovani ◽  
Barbara Borroni
Keyword(s):  
Response To Treatment ◽  
The European Union ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Disease Staging ◽  
Type C ◽  
Niemann Pick ◽  
New Treatments ◽  
Pick Disease ◽  
Disease Pathways

Niemann–Pick disease type C (NPC) is a rare autosomal recessive lysosomal storage disorder with extensive biological, molecular, and clinical heterogeneity. Recently, numerous studies have tried to shed light on the pathophysiology of the disease, highlighting possible disease pathways common to other neurodegenerative disorders, such as Alzheimer’s disease and frontotemporal dementia, and identifying possible candidate biomarkers for disease staging and response to treatment. Miglustat, which reversibly inhibits glycosphingolipid synthesis, has been licensed in the European Union and elsewhere for the treatment of NPC in both children and adults. A number of ongoing clinical trials might hold promise for the development of new treatments for NPC. The objective of the present work is to review and evaluate recent literature data in order to highlight the latest neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC pathophysiology. Furthermore, ongoing developments in disease-modifying treatments will be briefly discussed.

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 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 Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

2017 ◽  
Vol 2 ◽  
pp. 76 ◽  
Author(s):  
Elena-Raluca Nicoli ◽  
David Smith ◽  
Lauren Morris ◽  
Frances M. Platt
Keyword(s):  
Bile Acid ◽  
Mouse Model ◽  
Acid Treatment ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Cholanic Acid ◽  
Pick Disease

Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and in post-mortem liver from NPC patients. As bile acids regulate the P450 system, we tested bile acid treatment using ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, which is used to treat several cholestatic disorders. In this study, we compared UDCA treatment with the bile acid cholic acid (CA), and found unexpected hepatotoxicity in response to CA in Npc1 mice, but not to UDCA, suggesting that only UDCA should be used as an adjunctive therapy in NPC patients.

Niemann-Pick Disease Type C with Isolated Splenomegaly: A Case Report in a Child

2021 ◽  
Author(s):  
Bruna Ribeiro Torres ◽  
Daniela Otoni Russo ◽  
Vinícius Andrade Gomes Vuolo ◽  
Tarcísio Silva Borborema ◽  
André Vinícius Soares Barbosa ◽  
...  
Keyword(s):  
Autosomal Recessive Inheritance ◽  
Signs And Symptoms ◽  
Disease Type ◽  
Sphingolipid Metabolism ◽  
Neurological Involvement ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

AbstractNiemann-Pick disease type C is an innate error of lysosomal storage metabolism with an autosomal recessive inheritance pattern. The disease causes intracellular cholesterol accumulation and changes in sphingolipid metabolism. If cholesterol accumulates, the signs and symptoms of visceral involvement predominate. Neurological involvement results from sphingolipid accumulation. A 7-year-old student was referred to a tertiary service for the investigation of asymptomatic splenomegaly. Following an extensive examination, he was diagnosed with Niemann-Pick disease type C. Interestingly, this case's only symptom was splenomegaly.

scholarly journals Lipid mediated inhibition of Niemann-Pick C1 protein is an evolutionary conserved feature of multiple Mycobacterium lineages and non-tubercular mycobacteria.

2021 ◽  
Author(s):  
Frances M. Platt ◽  
Yuzhe Weng ◽  
Dawn Shepherd ◽  
Yi Lu ◽  
Nitya Krishnan ◽  
...  
Keyword(s):  
Cell Wall ◽  
Defense Mechanisms ◽  
Mycobacterium Abscessus ◽  
Specific Cell ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Mycobacterial Cell Wall ◽  
Pick Disease

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and is a major cause of human morbidity and mortality. Crucially, Mtb can persist and replicate within host macrophages (MF) and subvert multiple antimicrobial defense mechanisms. How this is achieved is incompletely understood. Previously, we reported that lipids shed by persistent mycobacteria inhibit NPC1, the lysosomal protein deficient in most cases of the rare, inherited lysosomal storage disorder Niemann-Pick disease type C (NPC). Inhibition of NPC1 leads to a drop in lysosomal calcium levels blocking phagosome-lysosome fusion and thereby leads to mycobacterial persistence. Studies of mycobacterial lineages have identified events during mycobacterial evolution that result in the acquisition of persistence. We speculated that the production of specific cell wall lipid(s) capable of inhibiting NPC1 activities could have been a critical step in the evolution of pathogenicity. In this study, we have therefore investigated whether lipid extracts from clinical Mtb strains representative of multiple Mtb lineages, members of the Mtb complex (MTBC) and selected non-tubercular mycobacteria (NTM) inhibit the NPC pathway. We have found that the ability to inhibit the NPC pathway was present in all clinical isolates studied from Mtb lineages 1, 2 and 4. We also found that lipids from MTBC member, Mycobacterium bovis and the NTM, Mycobacterium abscessus and Mycobacterium avium also inhibited the NPC pathway. However, when lipids were assayed from Mycobacterium canettii (M. canettii), a smooth tubercle mycobacterium, which is considered to resemble the common ancestor of the MTBC no inhibition of the NPC1 pathway was detected. We therefore conclude that the evolution of mycobacterial cell wall lipids that inhibit the NPC pathway evolved early and post divergence from M. canettii related mycobacteria and NPC1 inhibition significantly contributes to the ability of these pathogens to persist and cause disease.

scholarly journals Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

2018 ◽  
Vol 2 ◽  
pp. 76
Author(s):  
Elena-Raluca Nicoli ◽  
Mylene Huebecker ◽  
David Smith ◽  
Lauren Morris ◽  
Frances M. Platt
Keyword(s):  
Bile Acid ◽  
Mouse Model ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Npc Mouse ◽  
Cholanic Acid ◽  
Pick Disease

Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and also in post-mortem liver from NPC patients. We demonstrated the ability of the hydrophobic bile acid ursodeoxycholic acid (UDCA) (3α, 7β-dihydroxy-5β-cholanic acid) to correct the P450 system suppression. UDCA is used to treat several cholestatic disorders and was tested in NPC due to the P450 system being regulated by bile acids. Here, we compare the effect of UDCA and cholic acid (CA), another bile acid, in the NPC mouse model. We observed unexpected hepatotoxicity in response to CA treatment of NPC mice. No such hepatotoxicity was associated with UDCA treatment. These results suggest that CA treatment is contraindicated in NPC patients, whilst supporting the use of UDCA as an adjunctive therapy in NPC patients.

scholarly journals Unbiased yeast screens identify cellular pathways affected in Niemann–Pick disease type C

2020 ◽  
Vol 3 (7) ◽  
pp. e201800253
Author(s):  
Alexandria Colaco ◽  
María E Fernández-Suárez ◽  
Dawn Shepherd ◽  
Lihi Gal ◽  
Chen Bibi ◽  
...  
Keyword(s):  
Metal Ion ◽  
Ion Homeostasis ◽  
Disease Type ◽  
Nutrient Sensing ◽  
Lysosomal Storage ◽  
Metal Ion Homeostasis ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

Niemann–Pick disease type C (NPC) is a rare lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in the NPC1 gene lead to the majority of clinical cases (95%); however, the function of NPC1 remains unknown. To gain further insights into the biology of NPC1, we took advantage of the homology between the human NPC1 protein and its yeast orthologue, Niemann–Pick C–related protein 1 (Ncr1). We recreated the NCR1 mutant in yeast and performed screens to identify compensatory or redundant pathways that may be involved in NPC pathology, as well as proteins that were mislocalized in NCR1-deficient yeast. We also identified binding partners of the yeast Ncr1 orthologue. These screens identified several processes and pathways that may contribute to NPC pathogenesis. These included alterations in mitochondrial function, cytoskeleton organization, metal ion homeostasis, lipid trafficking, calcium signalling, and nutrient sensing. The mitochondrial and cytoskeletal abnormalities were validated in patient cells carrying mutations in NPC1, confirming their dysfunction in NPC disease.

scholarly journals Effects of curcumin nanoformulations on cellular function in Niemann-Pick disease type C astrocytes

2017 ◽  
Author(s):  
Emily Maguire ◽  
Luke J. Haslett ◽  
Joanne L. Welton ◽  
Helen Waller-Evans ◽  
Jule Goike ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Disease Type ◽  
Lipid Storage ◽  
Lysosomal Storage ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
And Function ◽  
Pick Disease

AbstractNiemann-Pick disease type C1 (NPC disease) is a neurodegenerative multi-lipid lysosomal storage disease caused by mutations in the NPC1 gene presenting with reduced lysosomal Ca2+ signalling and inhibited late endosome-lysosome transport. Elevating cytosolic Ca2+ levels in NPC cells has been shown to reduce lysosomal lipid storage. Treating Npc1-/- mice with the Ca2+ modulator curcumin led to reduced lipid storage, improved life expectancy and function. These studies led to reported utilisation of curcumin supplements by NPC disease families despite there being no clinical evidence of benefit and a report indicating no benefit of nanoformulated curcumin in Npc1-/- mice. The aim of this study was to determine whether various commercially available curcumin nanoformulations were capable of reproducing the findings obtained with unformulated pharmaceutical grade curcumin. We compared seven curcumin nanoformulations in Npc1-/- mouse astrocytes. All the nanoformulations elevate cytosolic Ca2+ levels but only two lowered lysosomal lipid storage. Importantly, some caused elevations in NPC lysosomal storage and/or decreased cellular viability. Although this is an in vitro study, our findings suggest that care should be taken when contemplating the use of curcumin supplements for NPC disease.

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