Olfaction impairment in lysosomal storage disorders: insights from a mouse model of Niemann Pick type C disease

Deficits in the detection, discrimination and identification of odors outline the impairment in the olfaction sensory modality in a number of neurodegenerative diseases. Although the assessment of olfaction in patients affected by lysosomal storage disorders is poorly characterized, olfactory deficits have been reported in Niemann Pick C (NPC) mouse models and Gaucher patients. Over recent years, using Niemann Pick C (NPC) disease mouse models we have provided evidence that defective intracellular cholesterol mobilization disturbs the proliferation/differentiation of neuronal and glial cells by affecting Shh-mediated signaling at the primary cilium. We reasoned that the olfactory bulb (OB) might be altered in NPC mouse because: i) the refinement of its circuitry with newly generated granule neurons (GNs) and olfactory sensory neurons (OSNs) relies on Shh; ii) Shh is found in dendrites of OSNs and in nasal mucus where OSN cilia are immersed; iii) clinical studies have correlated hyposmia to low level of Shh in nasal mucosa and dysosmia to Smo inhibition; and, iv) Shh signaling regulates the mobilization of odorant receptors (ORs) to the cilia where odorant detection is initiated. We have disclosed a down regulation of olfactory receptor activation in pre-symptomatic Npc1 mice compared to wt, as indicated by the significant reduction of S100A5 expression, which is among the first genes activated following odor stimulation of ORs. Consistently, the expression of various OR subtypes, including MOR23, MOR28, OR73, M72 and P2 were found robustly reduced starting from PN15. Taking advantage of BrdU labeling for tracing newborn GNs and the expression of specific markers of their functional maturation, i.e. tyrosine hydroxylase, calbindin, paravalbumin and calretinin, we have found that the relative fraction of GN subtypes significantly varies between Npc1 and wt mice, causing a disorganization of OB circuitry. How this impinges on olfactory abilities is being investigated by fine olfaction discrimination assessment.