Niemann-Pick disease type C1 causes early decline in olfaction

Niemann-Pick disease type C1 (NPC1) is a rare neurode- generative disease often resulting in progressive degener- ation and/or death of nerve cells. Its pathogenesis involves defective cholesterol biosynthesis and altered lipid homeo- stasis and storage. Although several neurological symptoms (motor and sen- sory) are associated with the disease, how it affects olfaction is only beginning to be understood. Recent work on a NPC1 mouse model have shown that knocking out the NPC1 gene causes deficits in the olfactory system. We addressed if olfactory deficits appear earlier in disease development compared to NPC1’s more severe manifest- ations (loss of motor function) similarly to other neurode- generative diseases (i.e. Parkinson, Alzheimer’s). In which case, the sense of smell could be used as a diagnostic tool to monitor the onset of the disease. Thus, we investigated the olfactory system of the NPC1-knock out mouse model at different post-natal days to characterize the disease pro- gression and to determine the time point at which the ab- sence of NPC1 is altering olfaction both morphologically and functionally. By combining immunohistochemistry and electrophysi- ology as well as behavioral tests, we found a progressive loss of mature olfactory receptor neurons in the olfactory epi- thelium of the NPC1-knock out mouse accompanied by a reduction in the magnitude of electro-olfactogram (EOG) odorant responses. In particular, we could observe a re- duction in the number of olfactory marker protein positive neurons as early as post-natal day 36 (P36). This time point is also when the odorant-induced EOG responses showed a significant reduction. Also, to monitor motor function we performed the rotarod test and the NPC1-knock out mice failed it only at a later time point while still showing a normal behavior at P36. In summary, our preliminary results show that the olfac- tory deficits can be detected before more deleterious neuro- logical symptoms at an early stage of the disease.