Olfactory dysfunction in a novel model of prodromal Parkinson’s disease in adult zebrafish

Olfactory dysfunction is an early clinical marker of prodromal Parkinson’s disease (PD), yet the underlying mechanisms remain unclear. To explore this relationship, we developed a zebrafish model that recapitulates prodromal PD-associated olfactory impairment without affecting motor function. We used zebrafish, due to their olfactory system’s similarity to mammals and their unique nervous system regenerative capacity. By injecting 6-hydroxydopamine (6-OHDA) into the dorsal telencephalic ventricle, we observed a significant loss of dopaminergic (DA) periglomerular neurons in the olfactory bulb (OB) and retrograde degeneration of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE). These alterations led to impaired responses to cadaverine, an aversive odorant, while responses to alanine, an attractive odorant, remained intact. 6-OHDA triggered robust neuroinflammatory responses that was attenuated by pranlukast, an anti-inflammatory drug. By 7 days post-injection, dopaminergic synapses in the OB were remodeled, OSNs in the OE appeared recovered, and neuroinflammation subsided, leading to full recovery of olfactory responses to cadaverine. These findings highlight zebrafish remarkable neuroplasticity and suggest this novel model of prodromal PD could provide valuable insights into early PD pathology. Understanding the interplay between dopaminergic loss, neuroinflammation, and olfactory dysfunction may inform therapeutic strategies for PD patients suffering from olfactory dysfunction.