Mutation of PrPc causes olfactory system defects during zebrafish development.

The relationship between PrP^c and PrP^sc conversion and neurodegeneration in prion diseases remains poorly understood. Although PrP^sc is associated with toxicity, symptom severity does not always correlate with PrP^sc levels and can occur in the absence of its accumulation. This suggests that aggregation alone is insufficient to cause disease, and that loss of PrP^c may also contribute to pathology. Although the physiological role of PrP^c is not fully understood, in vitro studies indicate its involved in neuronal differentiation and neuritogenesis. Disruption of these processes may replicate disease symptoms; however, supporting in vivo evidence is lacking.

This study aims to investigate the role of PrP in differentiation and neuritogenesis of zebrafish olfactory system during development. Olfaction is a key entry site for PrP^sc, where it undergoes replication, accumulation, transmission, and onset of symptoms. Zebrafish possess two PrP´s, PrP1 and PrP2, which are expressed in different tissues during embryogenesis. Notably, only PrP2 is expressed in the olfactory placode (OP) and olfactory bulb (OB). Mutants show a smaller OP, increased cell death, and impaired axonal formation in the OB. No delays in neuronal differentiation were observed, suggesting that neuritogenic defects result from a direct loss of PrP^c rather than impaired neuronal differentiation. Furthermore, mutants exhibited more, but shorter, axonal tracts in the OB, leading to structural abnormalities in olfactory glomeruli. These results support the hypothesis that PrP^c loss impairs neurodevelopment similarly to prion-related neurodegeneration. Overall, zebrafish olfactory system serves as a valuable model for exploring PrP^c role in neurodevelopment and disease.