近日,，一項刊登自國際雜志PNAS上的研究發(fā)現(xiàn),，通過改變一個氨基酸,，科研人員在一個實驗小鼠模型中引發(fā)了一種感染性朊病毒的自發(fā)形成,，并且重現(xiàn)了克雅二氏癥（CJD）的特征癥狀,。
朊病毒是折疊錯誤的蛋白質，它劫持了活細胞并逐漸破壞人類,、牛和其他哺乳動物的大腦組織,，根據(jù)朊病毒蛋白（PrP）突變具體位置的不同，它導致了差別很大的臨床癥狀,。Susan Lindquist及其同事比較了3種小鼠細胞系,，這些細胞系都表達了有單個氨基酸差異的同樣的朊病毒蛋白（PrP），從而研究兩種人類海綿狀腦病的單獨的遺傳差異,，這兩種病分別是克雅二氏癥（CJD）和致死性家族性失眠癥（FFI）,。
把兩種此前建立的小鼠系——一個正常的小鼠系和一個致死性家族性失眠癥（FFI）模型——與為這項實驗培育出的遺傳性克雅二氏癥（CJD）的模型進行了比較。該研究揭示,，表達這些突變朊病毒蛋白（PrP）的小鼠都自發(fā)產生了朊病毒,，可以在小鼠之間傳播，產生類似于人類克雅二氏癥（CJD）或致死性家族性失眠癥（FFI）的癥狀,。這組作者說,，這些發(fā)現(xiàn)揭示出，交換一個正?；蚪M的一個基因的單個氨基酸可以導致非常不同的神經退行性疾病,，并引發(fā)兩種不同的傳染性朊病毒的形成,。（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.
