From the Department of Biological Sciences and the Centre for Prion and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
From the Department of Biological Sciences and the Centre for Prion and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2E9, Canada
J Biol Chem. 2018 Aug 10;293(32):12576-12592. doi: 10.1074/jbc.RA117.001171. Epub 2018 Jun 14.
Normally folded prion protein (PrP) and its functions in healthy brains remain underappreciated compared with the intense study of its misfolded forms ("prions," PrP) during the pathobiology of prion diseases. This impedes the development of therapeutic strategies in Alzheimer's and prion diseases. Disrupting the zebrafish homologs of PrP has provided novel insights; however, mutagenesis of the zebrafish paralog did not recapitulate previous dramatic developmental phenotypes, suggesting redundancy with the paralog. Here, we generated zebrafish loss-of-function mutant alleles and dual mutants. Zebrafish and dual mutants resemble mammalian knockouts insofar as they lack overt phenotypes, which surprisingly contrasts with reports of severe developmental phenotypes when either or is knocked down acutely. Previous studies suggest that PrP participates in neural cell development/adhesion, including in zebrafish where loss of affects adhesion and deposition patterns of lateral line neuromasts. In contrast with the expectation that 's functions would be redundant to , they appear to have opposing functions in lateral line neurodevelopment. Similarly, loss of blunted the seizure susceptibility phenotypes observed in 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.
与对朊病毒疾病的病理生物学中错误折叠形式（“朊病毒”，PrP）的深入研究相比，正常折叠的朊病毒蛋白（PrP）及其在健康大脑中的功能仍未得到充分认识。这阻碍了阿尔茨海默病和朊病毒病治疗策略的发展。破坏斑马鱼 PrP 的同源物提供了新的见解；然而，斑马鱼 基因的突变并没有再现以前的显著发育表型，这表明与 基因的冗余。在这里，我们生成了斑马鱼 功能丧失突变等位基因和双 突变体。斑马鱼 和双 突变体与哺乳动物 敲除体相似，因为它们没有明显的表型，这与急性敲除 或 时出现严重发育表型的报道形成鲜明对比。先前的研究表明，PrP 参与神经细胞的发育/黏附，包括在斑马鱼中， 缺失会影响侧线神经丘的黏附和沉积模式。与“的功能可能与 冗余”的预期相反，它们似乎在侧线神经发育中具有相反的功能。同样， 缺失削弱了在 突变体中观察到的癫痫易感性表型，与如果这些朊病毒基因的等位基因具有冗余作用，则表型预计会加剧形成鲜明对比。总之，朊病毒突变鱼缺乏以前预测的明显表型，而是具有类似于哺乳动物的微妙表型。在斑马鱼朊病毒基因的等位基因中没有发现功能冗余的证据，并且当每个基因被单独破坏时观察到的表型与朊病毒蛋白在神经发育和神经活动调节中的古老功能一致。
