scholarly journals Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

2021 ◽  
Vol 22 (14) ◽  
pp. 7292
Author(s):  
Luca Marsili ◽  
Jennifer Sharma ◽  
Alberto J. Espay ◽  
Alice Migazzi ◽  
Elhusseini Abdelghany ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia Type ◽  
Niemann Pick Disease ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
History Of ◽  
Ataxia Syndrome ◽  
Niemann Pick

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

Acid and neutral sphingomyelinases: roles and mechanisms of regulation

2004 ◽  
Vol 82 (1) ◽  
pp. 27-44 ◽  
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).

scholarly journals Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene

2015 ◽  
Vol 28 (7-8) ◽  
Author(s):  
Jose Bernardo Quintos ◽  
Michael H. Guo ◽  
Andrew Dauber
Keyword(s):  
Short Stature ◽  
Adult Height ◽  
Frameshift Mutation ◽  
Index Case ◽  
Bone Age ◽  
Heterozygous Mutation ◽  
Maternal Grandfather ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
History Of

AbstractRecently, whole exome sequencing identified heterozygous defects in the aggrecan (We report a novel frameshift mutation inWe present a 5 1/2-year-old male with a family history of short stature in three generations. The maternal grandfather stands 144.5 cm (Ht SDS –4.7), mother 147.7 cm (Ht SDS –2.6), and index case 99.2 cm (Ht SDS –2.7). Our prepubertal patient has significant bone age advancement (bone age 8 years at chronologic age 5 1/2 years) resulting in a poor predicted adult height of 142 cm (Ht SDS –5.1). DNA sequencing identified a novel heterozygous variant inMutations in the

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.

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

2014 ◽  
Vol 26 (4) ◽  
pp. 609 ◽  
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.

Optical non-invasive detection of Niemann-Pick disease in vitro and in vivo

2017 ◽  
Vol 120 (1-2) ◽  
pp. S71
Author(s):  
Prakrit V. Jena ◽  
Thomas V. Galassi ◽  
Daniel Roxbury ◽  
Robert E. Schwartz ◽  
Frederick R. Maxfield ◽  
...  
Keyword(s):  
Non Invasive ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

scholarly journals Case Study on Type A Niemann Pick Disease

2016 ◽  
Vol 11 (04) ◽  
pp. 36-38
Author(s):  
S. Sriram ◽  
Jaleel Ahmed ◽  
Saranya Saminathan ◽  
Sweatha Annie ◽  
Silpa Raj
Keyword(s):  
Type A ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

scholarly journals Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

2021 ◽  
Vol 15 ◽  
Author(s):  
Lien Van Hoecke ◽  
Caroline Van Cauwenberghe ◽  
Kristina Dominko ◽  
Griet Van Imschoot ◽  
Elien Van Wonterghem ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Premature Death ◽  
Loss Of Function ◽  
Lipid Storage Disease ◽  
Niemann Pick Disease ◽  
Progressive Neurodegeneration ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer’s, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer’s disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1–/– mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1–/– choroid plexus explants are able to induce typical brain pathology characteristics of NPC1–/–, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.

scholarly journals In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C

2019 ◽  
Vol 20 (5) ◽  
pp. 1152 ◽  
Author(s):  
Nushrat Yasmin ◽  
Yoichi Ishitsuka ◽  
Madoka Fukaura ◽  
Yusei Yamada ◽  
Shuichi Nakahara ◽  
...  
Keyword(s):  
Free Cholesterol ◽  
Disease Type ◽  
Cholesterol Trafficking ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Deficient Mice ◽  
Pick Disease

Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-β-cyclodextrin (G2-β-CD) as a drug candidate against NPC. The physicochemical properties of G2-β-CD as an injectable agent were assessed, and molecular interactions between G2-β-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-β-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-β-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-β-CD formed higher-order inclusion complexes with free cholesterol. G2-β-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-β-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-β-CD (21.4 μmol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-β-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models.

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