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Prion protein is ubiquitinated after developing protease resistance in the brains of scrapie‐infected mice
Author(s) -
Kang ShinChung,
Brown David R,
Whiteman Matthew,
Li Ruliang,
Pan Tao,
Perry George,
Wisniewski Thomas,
Sy ManSun,
Wong BoonSeng
Publication year - 2004
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1555
Subject(s) - scrapie , ubiquitin , proteasome , biology , neurodegeneration , pathogenesis , protease , virology , transmissible spongiform encephalopathy , bovine spongiform encephalopathy , prion protein , immunology , microbiology and biotechnology , disease , pathology , genetics , enzyme , medicine , gene , biochemistry
Abstract Although the key event in the pathology of prion diseases is thought to be the conversion of cellular prion protein (PrP C ) to the protease‐resistant scrapie species termed PrP Sc , the factors that contribute to neurodegeneration in scrapie‐infected animals are poorly understood. One probable determinant could be when the accumulation of PrP Sc in infected brain overwhelms the ubiquitin–proteasome system and triggers the degenerative cascade. In the present study, it was found that in mouse brains infected with the ME7 scrapie strain, the level of ubiquitin protein conjugates increased significantly at ∼144 days post‐infection (pi) when clinical signs first become apparent. This elevation correlated with the detection of protease‐resistant PrP Sc and a decline in two endopeptidase activities associated with proteasome function. However, ubiquitination of PrP was only detected at the terminal stage, 3 weeks after the development of clinical symptoms (∼165 days pi). These results suggest that ubiquitination of PrP is a late event phenomenon and this conjugation occurs after the formation of protease‐resistant PrP Sc . Whether this post‐translational modification and the impairment of proteasome function are pivotal events in the pathogenesis of prion diseases remains to be determined. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.