Olfactory sensory map is perturbed in a human wild-type α-synuclein overexpressing transgenic mouse model of Parkinson’s disease

Olfactory dysfunction, often the earliest symptom of Parkinson's disease (PD), can precede clinical diagnosis by over 20 years, yet its mechanism and link to α-synuclein pathology remain unclear. To understand the impact of α-synuclein pathology on the topographic olfactory sensory map that supports the detection and discrimination of particular odors, we created two double transgenic mouse models (α-Syn/M72 and α-Syn/P2) expressing tagged-M72 or tagged-P2 odor receptors in a human wild-type α-synuclein over-expressing background. We demonstrated that the sensory map is disrupted in these mice. Histological analysis showed a significant reduction in M72 and P2 olfactory sensory neurons (OSNs), with altered glomerular topographies as axons converged into supernumerary glomeruli of varying size and location. These findings suggest that α-synuclein overexpression impairs the mechanism guiding the convergence of OSN axons and thus formation of a precise olfactory sensory map. As OSNs in the nasal epithelium are accessible via non-invasive biopsy, they are a potential source of prodromal PD biomarkers.