近日,一项刊登自国际杂志PNAS上的研究发现,通过改变一个氨基酸,科研人员在一个实验小鼠模型中引发了一种感染性朊病毒的自发形成,并且重现了克雅二氏症(CJD)的特征症状。
朊病毒是折叠错误的蛋白质,它劫持了活细胞并逐渐破坏人类、牛和其他哺乳动物的大脑组织,根据朊病毒蛋白(PrP)突变具体位置的不同,它导致了差别很大的临床症状。Susan Lindquist及其同事比较了3种小鼠细胞系,这些细胞系都表达了有单个氨基酸差异的同样的朊病毒蛋白(PrP),从而研究两种人类海绵状脑病的单独的遗传差异,这两种病分别是克雅二氏症(CJD)和致死性家族性失眠症(FFI)。
把两种此前建立的小鼠系——一个正常的小鼠系和一个致死性家族性失眠症(FFI)模型——与为这项实验培育出的遗传性克雅二氏症(CJD)的模型进行了比较。该研究揭示,表达这些突变朊病毒蛋白(PrP)的小鼠都自发产生了朊病毒,可以在小鼠之间传播,产生类似于人类克雅二氏症(CJD)或致死性家族性失眠症(FFI)的症状。这组作者说,这些发现揭示出,交换一个正常基因组的一个基因的单个氨基酸可以导致非常不同的神经退行性疾病,并引发两种不同的传染性朊病毒的形成。(生物谷Bioon.com)
doi:10.1073/pnas.1312006110
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Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases
Walker S. Jacksona,b,c,1, Andrew W. Borkowskia,b,c, Nicki E. Watsona, Oliver D. Kingd, Henryk Faase, Alan Jasanoffe,f, and Susan Lindquista,b,c,2
In man, mutations in different regions of the prion protein (PrP) are associated with infectious neurodegenerative diseases that have remarkably different clinical signs and neuropathological lesions. To explore the roots of this phenomenon, we created a knock-in mouse model carrying the mutation associated with one of these diseases [Creutzfeldt–Jakob disease (CJD)] that was exactly analogous to a previous knock-in model of a different prion disease [fatal familial insomnia (FFI)]. Together with the WT parent, this created an allelic series of three lines, each expressing the same protein with a single amino acid difference, and with all native regulatory elements intact. The previously described FFI mice develop neuronal loss and intense reactive gliosis in the thalamus, as seen in humans with FFI. In contrast, CJD mice had the hallmark features of CJD, spongiosis and proteinase K-resistant PrP aggregates, initially developing in the hippocampus and cerebellum but absent from the thalamus. A molecular transmission barrier protected the mice from any infectious prion agents that might have been present in our mouse facility and allowed us to conclude that the diseases occurred spontaneously. Importantly, both models created agents that caused a transmissible neurodegenerative disease in WT mice. We conclude that single codon differences in a single gene in an otherwise normal genome can cause remarkably different neurodegenerative diseases and are sufficient to create distinct protein-based infectious elements.