Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage

Tängemo, Carolina; Weber, Dominik; Theiß, Susanne; Mengel, Eugen; Runz, Heiko

doi:10.1194/jlr.p013524

Cited by 50 publications

(56 citation statements)

References 40 publications

(80 reference statements)

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“…1A) . This increase well exceeded the moderate increase in NPC1 protein levels upon knockdown of NPC2 , as previously observed in NPC2 -mutant fibroblasts (12,23). Unlike at the protein level, TMEM97 -siRNAs did not impact NPC1 mRNA levels (Supplementary Material, Fig.…”

Section: Resultssupporting

confidence: 81%

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

et al. 2016

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Niemann-Pick type C disease (NP-C) is a progressive lysosomal lipid storage disease caused by mutations in the NPC1 and NPC2 genes. NPC1 is essential for transporting cholesterol and other lipids out of lysosomes, but little is known about the mechanisms that control its cellular abundance and localization. Here we show that a reduction of TMEM97, a cholesterol-responsive NPC1-binding protein, increases NPC1 levels in cells through a post-transcriptional mechanism. Reducing TMEM97 through RNA-interference reduces lysosomal lipid storage and restores cholesterol trafficking to the endoplasmic reticulum in cell models of NP-C. In TMEM97 knockdown cells, NPC1 levels can be reinstated with wild type TMEM97, but not TMEM97 missing an ER-retention signal suggesting that TMEM97 contributes to controlling the availability of NPC1 to the cell. Importantly, knockdown of TMEM97 also increases levels of residual NPC1 in NPC1-mutant patient fibroblasts and reduces cholesterol storage in an NPC1-dependent manner. Our findings propose TMEM97 inhibition as a novel strategy to increase residual NPC1 levels in cells and a potential therapeutic target for NP-C.

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Section: Resultssupporting

confidence: 81%

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

et al. 2016

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“…Although, all three predictive packages indicate both p.N222S and p.N961S to be non-pathogenic these two variants have been reported in “visceral-only” or adult-onset NPC1 cases. The p.N222S variant was reported in combination with a p.I1061T mutation in a single adult onset (35 yr) patient with variant filipin staining 32 . This patient initially presented with visceral disease (hepatosplenomegaly) and later manifested ataxia at 44 years of age.…”

Section: Resultsmentioning

confidence: 96%

High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets

Wassif

Cross

Iben

et al. 2016

Genetics in Medicine

179

138

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PurposeNiemann-Pick disease, type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. Ascertainment is likely incomplete due to both these factors and that the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and development of potential therapies, it is important to understand the incidence of NPC and to define at risk patient populations.MethodWe evaluated data from four large massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or non-pathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency.ResultsOur data suggests an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. However, evaluation of common NPC1 variants, suggests that there may be a late-onset NPC1phenotype with a markedly higher incidence on the order of 1/20,000-39,000.ConclusionsWe determined a combined incidence of classical NPC of 1/89,229 or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients.

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“…Isobaric Labeling-based Quantitative Proteome Profiling of NPC1 I1061T and NPC1 WT Cells-Fibroblasts derived from skin of NPC1 patients exhibit profound and reproducible cholesterol accumulation in LE/Ly compartments, and therefore, provide a robust in vitro cellular model to study NPC1 disease (17). In an effort to investigate the relative expression level of proteins in NPC1…”

Section: Resultsmentioning

confidence: 99%

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

Rauniyar¹,

Subramanian

Lavallée‐Adam³

et al. 2015

Molecular & Cellular Proteomics

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Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in the late endosomal/lysosomal compartments. Mutations in the NPC1 protein are implicated in 95% of patients with NPC disease. The most prevalent mutation is the missense mutation I1061T that occurs in ϳ15-20% of the disease alleles. In our study, an isobaric labeling-based quantitative analysis of proteome of NPC1I1061T primary fibroblasts when compared with wild-type cells identified 281 differentially expressed proteins based on stringent data analysis criteria. Gene ontology enrichment analysis revealed that these proteins play important roles in diverse cellular processes such as protein maturation, energy metabolism, metabolism of reactive oxygen species, antioxidant activity, steroid metabolism, lipid localization, and apoptosis. The relative expression level of a subset of differentially expressed proteins (TOR4A, DHCR24, CLGN, SOD2, CHORDC1, HSPB7, and GAA) was independently and successfully substantiated by Western blotting. We observed that treating NPC1I1061T cells with four classes of seven different compounds that are potential NPC drugs increased the expression level of SOD2 and DHCR24. We have also shown an abnormal accumulation of glycogen in NPC1 I1061T fibroblasts possibly triggered by defective processing of lysosomal alpha-glucosidase. Our study provides a starting point for future more focused investigations to better understand the mechanisms by which the reported dysregulated proteins triggers the pathological cascade in NPC, and furthermore, their effect upon therapeutic interventions.

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Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage

Cited by 50 publications

References 40 publications

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells

High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets

Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann–Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis*

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