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| Poster #201 Unveiling the Sulfur Scent: The Impact of Copper Metabolism on Olfactory Dysfunction in Wilson's Disease |
| Shania Appadoo1, Mona Marie1, Maira H. Nagai1, Martina Ralle2, Hiroaki Matsunami1 1Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, United States 2Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, United States |
Wilson’s disease (WD) is a genetic disorder caused by mutations in the copper transporter ATP7B, resulting in toxic copper accumulation in the brain and liver. Notably, WD patients often exhibit specific anosmia, particularly for sulfur-containing odorants such as skunk spray and tert-butyl mercaptan (TBM), the odorant added to natural gas. This unique symptom hints at a potential link between copper metabolism and olfactory function, a connection that remains poorly understood. Using an ATP7B constitutive knockout mouse model of WD, our findings support the hypothesis that copper is essential for detecting sulfur-containing odors in vivo. Olfactory neurons expressing odorant receptors (ORs) responsive to TBM exhibit robust activation in wild-type mice but not in ATP7B knockout mice. Copper levels are dramatically reduced in the olfactory epithelium of ATP7B knockout mice, and ATP7B is expressed in a subpopulation of olfactory cells. To further investigate the local effects of ATP7B deletion on copper homeostasis and olfactory neuron function, we generated cell type-specific ATP7B knockout mice using Ascl3-Cre mouse strains. In this model, no significant differences in copper levels in the olfactory epithelium were observed between wild-type and ATP7B conditional knockout mice. Additionally, olfactory neurons expressing Or2t48 were activated by TBM in both wild-type and ATP7B conditional knockout mice. This study advances our understanding of how copper metabolism impacts sensory systems, particularly olfactory function. Furthermore, it emphasizes the translational potential of olfactory biomarkers in diagnostics and therapeutics. |