Using Protein Misfolding Cyclic Amplification Generates a Highly Neurotoxic PrP Dimer Causing Neurodegeneration
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Under the “protein-only” hypothesis, prion-based diseases are proposed to result from an infectious agent that is an abnormal isoform of the prion protein in the scrapie form, PrPSc. However, since PrPSc is highly insoluble and easily aggregates in vivo, this view appears to be overly simplistic, implying that the presence of PrPSc may indirectly cause neurodegeneration through its intermediate soluble form. We generated a neurotoxic PrP dimer with partial pathogenic characteristics of PrPSc by protein misfolding cyclic amplification in the presence of 1-palmitoyl-2-oleoylphosphatidylglycerol consisting of recombinant hamster PrP (23–231). After intracerebral injection of the PrP dimer, wild-type hamsters developed signs of neurodegeneration. Clinical symptoms, necropsy findings, and histopathological changes were very similar to those of transmissible spongiform encephalopathies. Additional investigation showed that the toxicity is primarily related to cellular apoptosis. All results suggested that we generated a new neurotoxic form of PrP, PrP dimer, which can cause neurodegeneration. Thus, our study introduces a useful model for investigating PrP-linked neurodegenerative mechanisms.
KeywordsPrion PrP dimer PMCA PrPSc PrP
This work was supported by the Natural Science Foundation of China (projects 31001048, 31172293, and 31272532), the Specialized Research Fund for the Doctoral Program of Higher Education and (SRFDP, project 20100008120002), the Foundation of Chinese Ministry of Science and Technology (project 2011BAI15B01), and the Program for Cheung Kong Scholars and Innovative Research Team in University of China (IRT0866).
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