Research Paper Volume 5, Issue 3 pp 155—173
Protease-sensitive prions with 144-bp insertion mutations
- 1 Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
- 2 Department of Neurology, Case Western Reserve University, Cleveland, OH 44106, USA
- 3 National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 44106, USA
- 4 National Center for Regenerative Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- 5 Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA
- 6 State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
- 7 First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province, China
Received: January 29, 2013 Accepted: February 27, 2013 Published: February 28, 2013
https://doi.org/10.18632/aging.100543How to Cite
Abstract
Insertion of 144-base pair (bp) containing six extra octapeptide repeats between residues 51 and 91 of prion protein (PrP) gene is associated with inherited prion diseases. Most cases linked to this insertion examined by Western blotting showed detectable proteinase K-resistant PrPSc (rPrPSc) resembling PrPSc type 1 and type 2 in sporadic Creutzfeldt-Jakob disease (sCJD), or PrP7-8 in Gerstmann-Sträussler-Scheinker disease. However, cases lacking detectable rPrPSc also have been reported. Which PrP conformer is associated with neuropathological changes in the cases without detectable rPrPSc remains to be determined. Here we report that while all six but one subjects with the 144-bp insertion mutations examined display the pathognomonic PrP patches in the cerebellum, one of them exhibits no detectable typical rPrPSc even in PrPSc-enriched preparations. Instead, a large amount of abnormal PrP is captured from this case by gene 5 protein and sodium phosphotungstate, reagents that have been proved to specifically capture abnormal PrP. All captured abnormal PrP from the cerebellum and other brain regions is virtually sensitive to PK-digestion (termed sPrPSc). The presence of the predominant sPrPSc but absence of rPrPSc in this 144-bp insertion-linked inherited CJD case suggests that mutant sPrPSc is the main component of the PrP deposit patches and sPrPSc is sufficient to cause neurotoxicity and prion disease.