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Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1

Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegener...

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Autores principales: Meyer, Anja, Wree, Andreas, Günther, René, Holzmann, Carsten, Schmitt, Oliver, Rolfs, Arndt, Witt, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412361/
https://www.ncbi.nlm.nih.gov/pubmed/28383485
http://dx.doi.org/10.3390/ijms18040777
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author Meyer, Anja
Wree, Andreas
Günther, René
Holzmann, Carsten
Schmitt, Oliver
Rolfs, Arndt
Witt, Martin
author_facet Meyer, Anja
Wree, Andreas
Günther, René
Holzmann, Carsten
Schmitt, Oliver
Rolfs, Arndt
Witt, Martin
author_sort Meyer, Anja
collection PubMed
description Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1(−/−) mutant mice compared with healthy controls (NPC1(+/+)). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1(−/−) mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in NPC1(−/−) mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1(+/+) controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.
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spelling pubmed-54123612017-05-05 Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1 Meyer, Anja Wree, Andreas Günther, René Holzmann, Carsten Schmitt, Oliver Rolfs, Arndt Witt, Martin Int J Mol Sci Article Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1(−/−) mutant mice compared with healthy controls (NPC1(+/+)). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1(−/−) mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in NPC1(−/−) mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1(+/+) controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1. MDPI 2017-04-06 /pmc/articles/PMC5412361/ /pubmed/28383485 http://dx.doi.org/10.3390/ijms18040777 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Meyer, Anja
Wree, Andreas
Günther, René
Holzmann, Carsten
Schmitt, Oliver
Rolfs, Arndt
Witt, Martin
Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1
title Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1
title_full Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1
title_fullStr Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1
title_full_unstemmed Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1
title_short Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1
title_sort increased regenerative capacity of the olfactory epithelium in niemann–pick disease type c1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412361/
https://www.ncbi.nlm.nih.gov/pubmed/28383485
http://dx.doi.org/10.3390/ijms18040777
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