Abstract
Introduction: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of Npc1 gene function that leads to progressive neurodegeneration. Here, we compared the pathologic effect of defective Npc1 gene on the vomeronasal neuroepithelium (VNE) with that of the olfactory epithelium (OE) in an NPC1 mouse model. Methods: Proliferation in the VNE and OE was assessed by applying a bromodeoxyuridine (BrdU) protocol. We further compared the immunoreactivities of anti-olfactory marker protein (OMP), and the lysosomal marker cathepsin-D in both epithelia. To investigate if degenerative effects of both olfactory systems can be prevented or reversed, some animals were treated with a combination of miglustat/allopregnanolone/2-hydroxypropyl-cyclodextrin (HPβCD), or a monotherapy with HPβCD alone. Results: Using BrdU to label dividing cells of the VNE, we detected a proliferation increase of 215% ± 12% in Npc1−/− mice, and 270% ± 10% in combination- treated Npc1−/− animals. The monotherapy with HPβCD led to an increase of 261% ± 10.5% compared to sham-treated Npc1−/− mice. Similar to the OE, we assessed the high regenerative potential of vomeronasal progenitor cells. OMP reactivity in the VNE of Npc1−/− mice was not affected, in contrast to that observed in the OE. Concomitantly, cathepsin-D reactivity in the VNE was virtually absent. Conclusion: Vomeronasal receptor neurons are less susceptible against NPC1 pathology than olfactory receptor neurons. Compared to control mice, however, the VNE of Npc1−/− mice displays an increased neuroregenerative potential, indicating compensatory cell renewal.
Highlights
Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has been documented in Niemann-Pick disease type C1 (NPC1)
We previously showed that survival of olfactory cells was increased and neurodegeneration prevented upon treatment with HPβCD and/or a substrate reduction therapy with miglustat/HPβCD/ allopregnanolone [27,28]
Basal precursor cells are not arranged in a distinct cell layer, like in the olfactory epithelium (OE), but occur basally, extending from the anterior and posterior margins to the central area over the entire epithelium
Summary
Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has been documented in Niemann-Pick disease type C1 (NPC1). Since olfactory acuity has been shown to be impaired in several neurodegenerative diseases such as Parkinson’s disease [23,24,25], we previously studied the sense of olfaction in NPC1 and noted severe structural, electrophysiological, and behavioral deficits [26,27] These alterations included considerable loss of ORN, the presence of autophagosomes, cathepsin-D (CathD)-positive lysosomal inclusions in all mucosal cells, and massive astrogliosis and microgliosis in the olfactory bulb. These findings were accompanied by a 45% increase of BrdU(+) proliferating cells in the olfactory mucosa, compared to wildtype controls [28]. In spite of this considerable attempt of proliferative compensation, the animals performed worse in a buried pellet test than normal controls [27]
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