In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.

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Human iNSC-derived brain organoid model of lysosomal storage disorder in Niemann–Pick disease type C

Cell Death and Disease ◽

10.1038/s41419-020-03262-7 ◽

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.

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

Journal of Pediatric Neurology ◽

10.1055/s-0040-1722209 ◽

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.

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

10.1101/135830 ◽

2017 ◽

Cited By ~ 1

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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A lysosomal storage disorder in mice: A model of Niemann-Pick disease

Journal of Inherited Metabolic Disease ◽

10.1007/bf02179154 ◽

1982 ◽

Vol 5 (4) ◽

pp. 239-240 ◽

Cited By ~ 21

Author(s):

T. Sakiyama ◽

M. Tsuda ◽

T. Kitagawa ◽

R. Fujita ◽

S. Miyawaki

Keyword(s):

Lysosomal Storage Disorder ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Storage Disorder ◽

Niemann Pick ◽

Pick Disease

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Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C

European Journal of Immunology ◽

10.1002/eji.201141821 ◽

2012 ◽

Vol 42 (7) ◽

pp. 1886-1892 ◽

Cited By ~ 12

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

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Acid and neutral sphingomyelinases: roles and mechanisms of regulation

Biochemistry and Cell Biology ◽

10.1139/o03-091 ◽

2004 ◽

Vol 82 (1) ◽

pp. 27-44 ◽

Cited By ~ 224

Author(s):

Norma Marchesini ◽

Yusuf A Hannun

Keyword(s):

Nitric Oxide ◽

Molecular Mechanisms ◽

Caveolin 1 ◽

Niemann Pick Disease ◽

Extracellular Stimuli ◽

Niemann Pick ◽

Hydrolysis Of ◽

Pick Disease

Ceramide, an emerging bioactive lipid and second messenger, is mainly generated by hydrolysis of sphingomyelin through the action of sphingomyelinases. At least two sphingomyelinases, neutral and acid sphingo myelinases, are activated in response to many extracellular stimuli. Despite extensive studies, the precise cellular function of each of these sphingomyelinases in sphingomyelin turnover and in the regulation of ceramide-mediated responses is not well understood. Therefore, it is essential to elucidate the factors and mechanisms that control the activation of acid and neutral sphingomyelinases to understand their the roles in cell regulation. This review will focus on the molecular mechanisms that regulate these enzymes in vivo and in vitro, especially the roles of oxidants (glu ta thi one, peroxide, nitric oxide), proteins (saposin, caveolin 1, caspases), and lipids (diacylglycerol, arachidonic acid, and ceramide).Key words: sphingomyelinase, ceramide, apoptosis, Niemann-Pick disease, FAN (factor associated with N-SMase activation).

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Clinical disease characteristics of patients with Niemann-Pick Disease Type C – findings from the International Niemann-Pick Disease Registry (INPDR)

10.21203/rs.3.rs-934191/v1 ◽

2021 ◽

Author(s):

Shaun Christopher Bolton ◽

Vina Soran ◽

Mercedes Pineda Marfa ◽

Jackie Imrie ◽

Paul Gissen ◽

...

Keyword(s):

Clinical Data ◽

Large Scale ◽

Disease Type ◽

Adult Onset ◽

Neurological Manifestations ◽

Disease Registry ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Pick Disease

Abstract Background Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). Method The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features. Results A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations; 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (VSGP) (70.9%), dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score according to neurological-onset. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, excluding ‘swallowing’ and ‘seizure’. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.43% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.94%), antidepressants (11.76%) and antacids (9.41%). Conclusion The proportion of participants at each age of neurological onset was relatively consistent across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

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Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1207-1 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 3

Author(s):

Caroline Hastings ◽

Camilo Vieira ◽

Benny Liu ◽

Cyrus Bascon ◽

Claire Gao ◽

...

Keyword(s):

Disease Type ◽

Lysosomal Storage ◽

Safety Issues ◽

Expanded Access ◽

Niemann Pick Disease ◽

The Us ◽

Progression Of Disease ◽

Report Analysis ◽

Niemann Pick ◽

Pick Disease

Abstract Background Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPβPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPβCD has been administered to NPC patients with approved INDs globally since 2009. Results Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPβCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPβCD following on average 13 months of IV HPβCD. Several patients transitioned to an alternate HPβCD. Moderately affected NPC patients treated with HPβCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. Conclusions These expanded access data support the safety and potential benefit of systemic IV administration of HPβCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPβCD in NPC patients.

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Spermatozoa from mice deficient in Niemann-Pick disease type C2 (NPC2) protein have defective cholesterol content and reduced in vitro fertilising ability

Reproduction Fertility and Development ◽

10.1071/rd12059 ◽

2014 ◽

Vol 26 (4) ◽

pp. 609 ◽

Cited By ~ 9

Author(s):

Dolores Busso ◽

María José Oñate-Alvarado ◽

Elisa Balboa ◽

Juan Castro ◽

Carlos Lizama ◽

...

Keyword(s):

Cholesterol Content ◽

Disease Type ◽

Wild Type ◽

Cholesterol Levels ◽

Niemann Pick Disease ◽

Epididymal Maturation ◽

Sperm Membrane ◽

Niemann Pick ◽

Pick Disease

The cholesterol content of the sperm membrane is regulated during both maturation in the epididymis and capacitation in the female tract, two processes required for the spermatozoa to acquire their fertilising ability. Because Niemann-Pick disease, type C2 (NPC2) protein is one of the most abundant components of the epididymal fluid and contains a functional cholesterol-binding site that can transfer cholesterol between membranes, it has been suggested for years that NPC2 could be involved in the regulation of cholesterol levels in spermatozoa during epididymal maturation. In the present study, western blot and immunohistochemistry analyses demonstrated significant levels of NPC2 in the mouse epididymal epithelium. Epididymal spermatozoa obtained from NPC2–/– mice were morphologically normal and had normal motility parameters, but had a reduced cholesterol content compared with that of wild-type (WT) spermatozoa, as determined by both biochemical and by flow cytometry analyses. These results suggest that NPC2 could be involved in regulating cholesterol levels in spermatozoa during epididymal maturation. To understand the relevance of epididymal NPC2 for sperm function, the ability of spermatozoa to undergo events influenced by epididymal maturation, such as capacitation and fertilisation, were compared between WT and NPC2–/– mice. Capacitated NPC2–/– spermatozoa exhibited defective tyrosine phosphorylation patterns and a reduced ability to fertilise cumulus–oocyte complexes compared with WT spermatozoa, supporting the relevance of mouse epididymal NPC2 for male fertility.

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