title: Using protein misfolding cyclic amplification generates a highly neurotoxic PrP dimer causing neurodegeneration.
abstract: 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, PrP(Sc). However, since PrP(Sc) is highly insoluble and easily aggregates in vivo, this view appears to be overly simplistic, implying that the presence of PrP(Sc) may indirectly cause neurodegeneration through its intermediate soluble form. We generated a neurotoxic PrP dimer with partial pathogenic characteristics of PrP(Sc) 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.
authors.affiliation: State Key Laboratories for Agrobiotechnology, Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: XiuJin
authors.initials: X
authors.lastname: Yang
authors.forename: LiFeng
authors.initials: L
authors.lastname: Yang
authors.forename: XiangMei
authors.initials: X
authors.lastname: Zhou
authors.forename: Sher Hayat
authors.initials: SH
authors.lastname: Khan
authors.forename: HuiNuan
authors.initials: H
authors.lastname: Wang
authors.forename: XiaoMin
authors.initials: X
authors.lastname: Yin
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yuan
authors.forename: ZhiQi
authors.initials: Z
authors.lastname: Song
authors.forename: WenYu
authors.initials: W
authors.lastname: Wu
authors.forename: DeMing
authors.initials: D
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D045744:Cell Line, Tumor; D006224:Cricetinae; D008647:Mesocricetus; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D010715:Phosphatidylglycerols / Q000737:chemistry; D018620:PrPSc Proteins / Q000633:toxicity*; D017096:Prion Diseases / Q000139:chemically induced / Q000473:pathology; D011328:Prions / Q000633:toxicity*; D015202:Protein Engineering; D017510:Protein Folding; D055503:Protein Multimerization
chemical_list: D010446:Peptide Fragments; D010715:Phosphatidylglycerols; D018620:PrPSc Proteins; D011328:Prions; C428437:prion protein (23-231); C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol