An unexpected insight into the cause of olfactory dysfunction: fibrillogenesis of odorant-binding proteins.

Olfactory dysfunction is a common complication of serious pathologies, including neurodegenerative disorders, bacterial and viral infections, including COVID-19, and others. Despite the widespread prevalence of olfactory disorders, the pathophysiological mechanisms of their development, as well as the molecular basis of their association with the underlying disease, remain incompletely understood. The current work formulates a new concept of the origin of olfactory disorders, linking a decrease in the activation of olfactory neurons and their death to the fibrillogenesis of odorant-binding proteins (OBPs), which are the primary participants of olfactory perception. The potential triggers of OBPs' amyloidogenesis in vivo are discussed, such as molecular crowding, components of nasal medications, environmental factors, and cross-seeding with viral and bacterial amyloids. Several ways of impairment of olfactory signaling as a result of fibrillogenesis of OBPs are formulated: complete loss of OBPs functionality following amyloid formation; mechanical blockage of the membranes of sensory neurons and damage to chemoreceptors on their surface, preventing olfactory signaling; cytotoxic effect of OBPs' amyloid on sensory neurons and other cells of the olfactory epithelium. The proposed concept offers a novel perspective on the pathogenesis of olfactory dysfunction, as well as its possible association with amyloidoses, including in neurodegenerations, and infectious diseases. It opens prospects for the development of new therapeutic approaches to the treatment of olfactory disorders.