Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

Helquist, Paul; Maxfield, Frederick R.; Wiech, N. L.; Wiest, Olaf

doi:10.1007/s13311-013-0217-2

Cited by 53 publications

(65 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The concentration of CYCLO required to mobilize LE/L cholesterol in NPC1-defi cient cells in either peripheral tissues or in the CNS of Npc1 Ϫ / Ϫ mice is <1 mM, ( 160,161 ). Because HDAC inhibitors increase the amount of NPC1 protein ( 162 ), these inhibitors might be useful in NPC patients in which residual NPC1 activity remains or where partially active NPC1 protein is mislocalized ( 163 ). The antiapoptotic agent imatinib has also been suggested as an agent that might prevent neurodegeneration in NPC disease by inhibiting the c-Abl pathway, the activity of which is increased in Npc1 Ϫ / Ϫ Purkinje cells ( 164 ( 60 ), although the pulmonary disease was resistant to CYCLO ( 60 ).…”

Section: Cyclodextrin As a Therapy For Npc Diseasementioning

confidence: 99%

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

Vance

Karten

2014

Journal of Lipid Research

146

125

View full text Add to dashboard Cite

Section: Cyclodextrin As a Therapy For Npc Diseasementioning

confidence: 99%

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

Vance

Karten

2014

Journal of Lipid Research

146

125

View full text Add to dashboard Cite

“…We assessed our TMT results by validating the expression level of seven proteins by Western blotting. From a therapeutic perspective, we monitored the expression of two DEPs, SOD2 and DHCR24, in the NPC1 I1061T fibroblasts upon treatment with potential NPC drugs: ␤-cycodextrins (M␤CD and HPCD) (9), histone deacetylase inhibitors (HDACIs, such as CI-994, SAHA, and VPA) (10), antioxidant N-acetyl cysteine (NAC), and an oxysterol derivative pharmacological chaperone, mo56HC (11). We have also examined the cellular glycogen levels in NPC1…”

Section: Niemann-pick Type C (Npc)mentioning

confidence: 99%

“…A fully automated 12-step MudPIT run was performed on each sample using a three mobile phase system consisting of buffer A (5% ACN; 0.1% FA), buffer B (80% ACN, 0.1% FA), and buffer C (500 mM ammonium acetate, 5% ACN, 0.1% FA). The first step was a 60 min reverse-phase run, whereas subsequent steps were of 120 min duration and included steps with 10,20,30,40,50,60,70,80,90, and 100% buffer C run for 4 min at the beginning of the gradient and a last step that includes salt bump of 90% buffer C with 10% buffer B for 4 min.…”

Section: Mass Spectrometry (Ms)mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…Other treatments for NPC are currently undergoing clinical trials (2‐hydroxypropyl‐β‐cyclodextrin 25, histone deacetylase inhibitors 26 and arimoclomol).…”

mentioning

confidence: 99%

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

Mazzacuva¹,

Mills²,

Mills³

et al. 2016

FEBS Letters

107

View full text Add to dashboard Cite

This article describes a rapid UPLC‐MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann‐Pick C (NPC). Two new compounds, NPCBA1 (3β‐hydroxy,7β‐N‐acetylglucosaminyl‐5‐cholenoic acid) and NPCBA2 (probably 3β,5α,6β‐trihydroxycholanoyl‐glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40‐ and 10‐fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker.

show abstract

Treatment of Niemann–Pick Type C Disease by Histone Deacetylase Inhibitors

Cited by 53 publications

References 109 publications

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

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

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

Contact Info

Product

Resources

About