Prion gene paralogs are dispensable for early zebrafish development but have non-additive roles in seizure susceptibility

Normally folded prion protein (PrPC) and its functions in healthy brains remain underappreciated compared to the intense study of its misfolded forms ("prions", PrPSc) during the pathobiology of prion diseases. This impedes development of therapeutic strategies in Alzheimer and Prion diseases. Disrupting the zebrafish homologs of PrPC has provided novel insights, however mutagenesis of the zebrafish paralog prp2 did not recapitulate previous dramatic developmental phenotypes, suggesting redundancy with the prp1 paralog. Here we generated zebrafish prp1 loss-of-function mutant alleles, and compound prp1-/- ;prp2-/- mutants. Zebrafish prp1-/- and compound prp1-/- ;prp2-/- mutants resemble mammalian Prnp knockouts insofar as they lack overt phenotypes, which surprisingly contrasts reports of severe developmental phenotypes when either prp1 or prp2 are knocked down acutely. Previous studies suggest that PrPC participates in neural cell development/adhesion, including in zebrafish where loss of prp2 affects adhesion and deposition pattern of lateral line neuromasts. Contrasting the expectation that functions of prp1 would be redundant to prp2, they appear to have opposing functions in lateral line neurodevelopment. Similarly, loss of prp1 blunted the seizure susceptibility phenotypes observed in prp2 mutants, contrasting the expected exacerbation of phenotypes if these prion gene paralogs were serving redundant roles. In sum, prion mutant fish lack the overt phenotypes previously predicted, and instead have subtle phenotypes similar to mammals. No evidence was found for functional redundancy in the zebrafish prion gene paralogs, and the phenotypes observed when each gene is disrupted individually are consistent with ancient functions of prion proteins in neurodevelopment and modulation of neural activity.