Neurodegeneration in the olfactory system in Niemann Pick type C1 disease

Abstract Niemann-Pick type C1 (NPC1) disease is a rare neurodegenerative disorder linked to defective cholesterol biosynthesis and altered lipid regulation. In patients, the most common variant in the Npc1 gene is a missense mutation that leads to a misfolded and non-functional NPC1 protein. We used a mouse model carrying this mutation (I1061T, Npc1 tm(I1061T)Dso ) to investigate the olfactory system since olfaction is often negatively impacted in many neurodegenerative disorders, with olfactory decline frequently preceding other neurodegenerative symptoms. We characterized cell types in the olfactory epithelium (OE) in wild-type, heterozygous, and homozygous Npc1 tm(I1061T)Dso mice to analyze neurodegeneration at two time points, namely 36 and 60 days after birth. In homozygous Npc1 tm(I1061T)Dso mice the density of olfactory sensory neurons (OSNs) at 36 days after birth is decreased compared to wild type and heterozygous mice while the density of immature OSNs and the stem cell niche seems to not be affected. In the OE of the homozygous Npc1 tm(I1061T)Dso mice we found an increased density of apoptotic cells and clear sign of neuroinflammation in macrophage/microglia infiltrating the OE. We analyzed the lipid profile of OE by positive MALDI-TOF and found increased markers of neuroinflammation homozygous Npc1 tm(I1061T)Dso mice. These structural changes affected the functionality of the OE since we found reduced odorant responses in Npc1 tm(I1061T)Dso mice compared to wild type. Additionally, our olfactory behavioral tests revealed deficits in odor-guided food-seeking tests in Npc1 tm(I1061T)Dso but not in the wild type and heterozygous mice. We also analyzed the olfactory abilities of a family of three with the parents carrying two different mutations of the Npc1 gene, with the child carrying both mutations and being diagnosed with NPC1 disease. Using the Sniffin’ Sticks olfactory test, we found that all three were hyposmic with the child having severe hyposmia. Our work extensively characterized the OE structurally and functionally proposing it as a sentinel to monitor disease progression. We are the first to show that NPC1 patients are affected by severe hyposmia and that heterozygous parents could be monitored for olfactory abilities since it could be a biomarker for future neurological disorders.