Breakage of PrP aggregates is essential for efficient autocatalytic propagation of misfolded prion protein

The conversion of cellular prion protein (PrP C) to the disease-associated misfolded isoform (PrP Sc) is an essential process for prion replication. This structural conversion can be modelled in protein misfolding cyclic amplification (PMCA) reactions in which PrP Sc is inoculated into healthy hamst...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2005-01, Vol.326 (2), p.339-343
Main Authors: Piening, Niklas, Weber, Petra, Giese, Armin, Kretzschmar, Hans
Format: Article
Language:English
Subjects:
Aggregation
Amyloid
Amyloidosis - metabolism
Animals
Breakage
Catalysis
Cricetinae
Neurodegeneration
PMCA
Prion
Prion Diseases - metabolism
Prion Diseases - transmission
Prions - chemistry
Prions - metabolism
Propagation
Protein Binding
Protein Denaturation
Protein Folding
PrPSc Proteins - chemistry
PrPSc Proteins - metabolism
Sonication
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Summary:The conversion of cellular prion protein (PrP C) to the disease-associated misfolded isoform (PrP Sc) is an essential process for prion replication. This structural conversion can be modelled in protein misfolding cyclic amplification (PMCA) reactions in which PrP Sc is inoculated into healthy hamster brain homogenate, followed by cycles of incubation and sonication. In serial transmission PMCA experiments it has recently been shown that the protease-resistant PrP obtained in vitro (PrPres) is generated by an autocatalytic mechanism. Here, serial transmission PMCA experiments were compared with serial transmission reactions lacking the sonication steps. We achieved approximately 200,000-fold PrPres amplification by PMCA. In contrast, although initial amplification was comparable to PMCA reactions, PrPres levels quickly dropped below detection limit when samples were not subjected to ultrasound. These results indicate that aggregate breakage is essential for efficient autocatalytic amplification of misfolded prion protein and suggest an important role of aggregate breakage in prion propagation.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2004.11.039