Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 32, Pages 12576-12592Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.001171
Keywords
neurodevelopment; zebrafish; prion disease; transcription activator-like effector nuclease; TALEN; PrPC; excitotoxicity; neurodegeneration; gene editing; neural hyperactivity; targeted mutagenesis
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Funding
- Alberta Prion Research Institute-Alberta Innovates BioSolutions
- Alzheimer Society of Alberta
- Northwest Territories
- Alzheimer Society of Canada
- Alberta Innovates Health Solutions
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Normally folded prion protein (PrPC) and its functions in healthy brains remain underappreciated compared with the intense study of its misfolded forms (prions, PrPSc) during the pathobiology of prion diseases. This impedes the development of therapeutic strategies in Alzheimer's 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 dual prp1(-/-);prp2(-/-) mutants. Zebrafish prp1(-/-) and dual prp1(-/-);prp2(-/-) mutants resemble mammalian Prnp knockouts insofar as they lack overt phenotypes, which surprisingly contrasts with reports of severe developmental phenotypes when either prp1 or prp2 is 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 patterns of lateral line neuromasts. In contrast with the expectation that prp1's functions 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 summary, prion mutant fish lack the overt phenotypes previously predicted, and instead they 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.
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