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Int. J. Mol. Sci. 2017, 18(4), 777; doi:10.3390/ijms18040777

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

1
Institute of Anatomy, University of Rostock, 18057 Rostock, Germany
2
Institute of Medical Genetics, Rostock University Medical Center, 18057 Rostock, Germany
3
Albrecht-Kossel Institute for Neuroregeneration, Rostock University Medical Center, 18147 Rostock, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Ritva Tikkanen
Received: 2 February 2017 / Revised: 19 March 2017 / Accepted: 20 March 2017 / Published: 6 April 2017
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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 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. View Full-Text
Keywords: immunohistochemistry; cyclodextrin; allopregnanolone; miglustat; NPC1; mouse model; olfactory mucosa; bromodeoxyuridine; olfactory marker protein immunohistochemistry; cyclodextrin; allopregnanolone; miglustat; NPC1; mouse model; olfactory mucosa; bromodeoxyuridine; olfactory marker protein
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Meyer, A.; Wree, A.; Günther, R.; Holzmann, C.; Schmitt, O.; Rolfs, A.; Witt, M. Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1. Int. J. Mol. Sci. 2017, 18, 777.

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