title: Increased Regenerative Capacity of the Olfactory Epithelium in Niemann-Pick Disease Type C1.
abstract: 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 ofNPC1-/-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 ofNPC1-/-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 inNPC1-/-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 treatedNPC1+/+controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.
authors.affiliation: Institute of Anatomy, University of Rostock, 18057 Rostock, Germany. anja.meyer@med.uni-rostock.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Meyer
authors.affiliation: Institute of Anatomy, University of Rostock, 18057 Rostock, Germany. andreas.wree@med.uni-rostock.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wree
authors.affiliation: Institute of Anatomy, University of Rostock, 18057 Rostock, Germany. ren.guenther@gmx.de.
authors.forename: René
authors.initials: R
authors.lastname: Günther
authors.affiliation: Institute of Medical Genetics, Rostock University Medical Center, 18057 Rostock, Germany. carsten.holzmann@med.uni-rostock.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Holzmann
authors.affiliation: Institute of Anatomy, University of Rostock, 18057 Rostock, Germany. schmitt@med.uni-rostock.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schmitt
authors.affiliation: Albrecht-Kossel Institute for Neuroregeneration, Rostock University Medical Center, 18147 Rostock, Germany. arndt.rolfs@med.uni-rostock.de.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: Institute of Anatomy, University of Rostock, 18057 Rostock, Germany. martin.witt@med.uni-rostock.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Witt
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000473:pathology; D009831:Olfactory Mucosa / Q000187:drug effects / Q000473:pathology*; D011280:Pregnanolone / Q000008:administration & dosage / Q000494:pharmacology; D011506:Proteins / Q000235:genetics*; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D017485:1-Deoxynojirimycin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C059896:miglustat; D011280:Pregnanolone
keywords: NPC1; allopregnanolone; bromodeoxyuridine; cyclodextrin; immunohistochemistry; miglustat; mouse model; olfactory marker protein; olfactory mucosa