Studies On Gene Polymorphisms Of The Buffalo Prion Protein Associated With Bovine Spongiform Encephalopathy Susceptibility

Prion diseases, also known as transmissible spongiform encephalopathies. are a group of invariably fatal neurodegenerative diseases. The diseases have been found in several species of mammals, such as Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle. These diseases pose a serious threat to human and animal health as well as to the social economic. Consequently, prion disease-associated studies have become a hotspot in the field of medicine and biology.The pathogenic factor of prion diseases is prion protein (PrP). Prion protein is encoded by the prion protein gene (PRNP) and plays an important role in the pathogenic mechanism of prion diseases. Previous studies have revealed that PRNP gene polymorphisms are relevant to the susceptibility of animal and human to prion diseases. The bovine PRNP polymorphisms that have been suggested to be related to BSE susceptibility include the following four aspects:1) a23-bp insertion/deletion (indel) polymorphism in the promoter region;2) a12-bp indel polymorphism in intron1;3) the number of octapeptide repeats (octarepeats) present in the coding sequences (CDS);4) amino acid polymorphisms in the CDS. Remarkably, BSE has never been reported in buffalo despite its close phylogenetic affinity to cattle, for which more than190,000cases of BSE have been reported to date (OIE statistics). Most of the previous studies are focused on the BSE-susceptible cattle, whereas, population level study of the PRNP genetic diversity in BSE-resistant buffalo is still rare.In this study, we investigated the frequency distributions of the above-mentioned four PRNP polymorphisms in312Chinese buffaloes covering8different breeds. Then, we pooled and analyzed all reported data of the23-and12-bp indel polymorphisms for healthy cattle, BSE cattle and buffalo breeds. After a comparative analysis of PRNP polymorphisms between buffalo and cattle, our results revealed three significant findings in buffalo:1) extraordinarily low deletion allele frequencies of the23-and12-bp indel polymorphisms;2) significantly lower allelic frequencies of six octarepeats in the CDS and3) the presence of S4R, A16V, P54S, G108S, V123M, S154N and F257L amino acid substitutions in buffalo CDSs. Compared with cattle, three fixed PrP mutations (S4R, A16V and V123M) were detected in buffalo. Furthermore, three alleles at the sites54S.154N, and257L have been fixed in buffalo, while very low frequencies are noted in cattle. Conversely, the position G108has been fixed in cattle, while93.1%buffaloes contain serine and the remaining examined animals contain glycine.Based on the study of the CDS of PRNP and the molecular characteristics of PrP conformational changes and aggregation in BSE, a molecular dynamics simulation was performed between wild-type and mutated (S154N) cattle PrP. These findings support the conclusion that mutation weakens the local aggregation trend and the conformation conversion. Consequently, the molecular dynamics simulation of PrP indicate that cattle are more susceptible to change conformation than buffalo, this is probably associated with BSE susceptibility in cattle. These findings suggested that the genetic differences in bovine PRNP may be responsible for the species-specific susceptibility to BSE. Our findings possibly hold the key to understanding the BSE susceptibility differences seen in these two closely related organisms.