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Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone

Niemann-Pick C disease (NPC) is an autosomal recessive neurodegenerative disorder caused by the abnormal function of NPC1 or NPC2 proteins, leading to an accumulation of unesterified cholesterol and glycosphingolipids (GSLs) in the lysosomes. The mechanisms underlying the pathophysiology in NPC dise...

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Autores principales: Zampieri, Stefania, Mellon, Synthia H, Butters, Terry D, Nevyjel, Marco, Covey, Douglas F, Bembi, Bruno, Dardis, Andrea
Formato: Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832077/
https://www.ncbi.nlm.nih.gov/pubmed/18774957
http://dx.doi.org/10.1111/j.1582-4934.2008.00493.x
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author Zampieri, Stefania
Mellon, Synthia H
Butters, Terry D
Nevyjel, Marco
Covey, Douglas F
Bembi, Bruno
Dardis, Andrea
author_facet Zampieri, Stefania
Mellon, Synthia H
Butters, Terry D
Nevyjel, Marco
Covey, Douglas F
Bembi, Bruno
Dardis, Andrea
author_sort Zampieri, Stefania
collection PubMed
description Niemann-Pick C disease (NPC) is an autosomal recessive neurodegenerative disorder caused by the abnormal function of NPC1 or NPC2 proteins, leading to an accumulation of unesterified cholesterol and glycosphingolipids (GSLs) in the lysosomes. The mechanisms underlying the pathophysiology in NPC disease are not clear. Oxidative damage is implicated in the pathophysiology of different neurological disorders and the effect of GSL accumulation on the intracellular redox state has been documented. Therefore, we determined whether the intracellular redox state might contribute to the NPC disease pathophysiology. Because the treatment of NPC mice with allopregnanolone (ALLO) increases their lifespan and delays the onset of neurological impairment, we analysed the effect of ALLO on the oxidative damage in human NPC fibroblasts. Concentrations of reactive oxygen species (ROS) and lipid peroxidation were higher in fibroblasts from NPC patients than in fibroblasts from normal subjects. Fibroblasts from NPC patients were more susceptible to cell death through apoptosis after an acute oxidative insult. This process is mediated by activation of the NF-κB signalling pathway. Knockdown of NPC1 mRNA both in normal fibroblasts and in human SH-SY5Y neuroblastoma cells caused increased ROS concentrations. ALLO treatment of fibroblasts from NPC patients or NPC1 knockdown cells reduced the levels of ROS and lipid peroxidation and prevented peroxide-induced apoptosis and NF-kB activation. Thus, these findings suggest that oxidative stress might contribute to the NPC disease and ALLO might be beneficial in the treatment of the disease, at least in part, due to its ability to restore the intracellular redox state.
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spelling pubmed-28320772010-09-01 Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone Zampieri, Stefania Mellon, Synthia H Butters, Terry D Nevyjel, Marco Covey, Douglas F Bembi, Bruno Dardis, Andrea J Cell Mol Med Molecular Medicine Niemann-Pick C disease (NPC) is an autosomal recessive neurodegenerative disorder caused by the abnormal function of NPC1 or NPC2 proteins, leading to an accumulation of unesterified cholesterol and glycosphingolipids (GSLs) in the lysosomes. The mechanisms underlying the pathophysiology in NPC disease are not clear. Oxidative damage is implicated in the pathophysiology of different neurological disorders and the effect of GSL accumulation on the intracellular redox state has been documented. Therefore, we determined whether the intracellular redox state might contribute to the NPC disease pathophysiology. Because the treatment of NPC mice with allopregnanolone (ALLO) increases their lifespan and delays the onset of neurological impairment, we analysed the effect of ALLO on the oxidative damage in human NPC fibroblasts. Concentrations of reactive oxygen species (ROS) and lipid peroxidation were higher in fibroblasts from NPC patients than in fibroblasts from normal subjects. Fibroblasts from NPC patients were more susceptible to cell death through apoptosis after an acute oxidative insult. This process is mediated by activation of the NF-κB signalling pathway. Knockdown of NPC1 mRNA both in normal fibroblasts and in human SH-SY5Y neuroblastoma cells caused increased ROS concentrations. ALLO treatment of fibroblasts from NPC patients or NPC1 knockdown cells reduced the levels of ROS and lipid peroxidation and prevented peroxide-induced apoptosis and NF-kB activation. Thus, these findings suggest that oxidative stress might contribute to the NPC disease and ALLO might be beneficial in the treatment of the disease, at least in part, due to its ability to restore the intracellular redox state. John Wiley & Sons, Ltd 2009-09 2008-09-04 /pmc/articles/PMC2832077/ /pubmed/18774957 http://dx.doi.org/10.1111/j.1582-4934.2008.00493.x Text en © 2008 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
spellingShingle Molecular Medicine
Zampieri, Stefania
Mellon, Synthia H
Butters, Terry D
Nevyjel, Marco
Covey, Douglas F
Bembi, Bruno
Dardis, Andrea
Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone
title Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone
title_full Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone
title_fullStr Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone
title_full_unstemmed Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone
title_short Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone
title_sort oxidative stress in npc1 deficient cells: protective effect of allopregnanolone
topic Molecular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832077/
https://www.ncbi.nlm.nih.gov/pubmed/18774957
http://dx.doi.org/10.1111/j.1582-4934.2008.00493.x
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