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Targeted Mutation of the Gene Encoding Prion Protein in Zebrafish reveals a Conserved Role in Neuron Excitability.
MedLine Citation:
PMID:  23523635     Owner:  NLM     Status:  Publisher    
The function of the cellular prion protein (PrP(C)) in healthy brains remains poorly understood, in part because Prnp knockout mice are viable. On the other hand, transient knockdown of Prnp homologs in zebrafish (including two paralogs, prp1 and prp2) has suggested that PrP(C) is required for CNS development, cell adhesion, and neuroprotection. It has been argued that zebrafish Prp2 is most similar to mammalian PrP(C), yet it has remained intransigent to the most thorough confirmations of reagent specificity during knockdown. Thus we investigated the role of prp2 using targeted gene disruption via zinc finger nucleases. Prp2(-/-) zebrafish were viable and did not display overt developmental phenotypes. Back-crossing female prp2(-/-) fish ruled out a role for maternal mRNA contributions. Prp2(-/-) larvae were found to have increased seizure-like behaviour following exposure to the convulsant pentylenetetrazol (PTZ), as compared to wild type fish. In situ recordings from intact hindbrains demonstrated that prp2 regulates closing of N-Methyl-D-aspartate (NMDA) receptors, concomitant with neuroprotection during glutamate excitotoxicity. Overall, the knockout of Prp2 function in zebrafish independently confirmed hypothesized roles for PrP, identifying deeply conserved functions in post-developmental regulation of neuron excitability that are consequential to the etiology of prion and Alzheimer diseases.
Valerie C Fleisch; Patricia L A Leighton; Hao Wang; Laura M Pillay; R Gary Ritzel; Ganive Bhinder; Birbickram Roy; Keith B Tierney; Declan W Ali; Andrew J Waskiewicz; W Ted Allison
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-3-21
Journal Detail:
Title:  Neurobiology of disease     Volume:  -     ISSN:  1095-953X     ISO Abbreviation:  Neurobiol. Dis.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-3-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9500169     Medline TA:  Neurobiol Dis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013. Published by Elsevier Inc.
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada; Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada.
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