A detergent-insoluble, partially proteinase K (PK)-resistant aggregated prion protein (PrPSc) constitutes the major component of prions that cause a group of fatal transmissible spongiform encephalopathies or prion diseases in animals and humans. PrPSc derives from a detergent-soluble and PK-sensitive cellular prion protein (PrPC) via a post-translational conformational transition of ?-helixes to ?-sheets in the protein molecule. Once generated, it continues to assimilate PrPC. Although the conversion of PrPC into PrPSc is known to be triggered by exogenous PrPSc seeds in the infectious prion disease, how it takes place in the spontaneous prion diseases, including sporadic and familial forms, remains unknown. According to the prevailing seeding model of PrPSc formation (Jarrett and Lansbury, 1993), the normal brain may contain a small amount of PrPSc or PrPSc precursor (PrP*) that triggers the conversion when it reaches a certain level in sporadic and familial prion diseases. We have recently provided the first experimental evidence that small amounts of detergent- insoluble PrP aggregates and PK-resistant PrP species (iPrP) are present in uninfected human and animal brains (Yuan et al., 2006). Moreover, uninfected cultured cells expressing either wild-type or pathogenic mutant human PrP also form PK-resistant PrP (Yuan et al., 2008). The long-term objective of this project is to investigate the in vivo pathways of conversion of brain PrPC into PrPSc. We hypothesize that iPrP, identified in uninfected brains, is a homologue of PrP*.
Three Specific Aims will be addressed in this study: 1) to investigate molecular mechanism of iPrP formation and characterize iPrP in cultured neurons expressing wild-type or mutant PrP and in the brain white matter of uninfected humans and animals using qualitative and quantitative analysis including proteasome inhibition, gel filtration, protein N-terminal sequencing, and Western blotting;2) to examine whether iPrP can be amplified and whether the conversion of PrPC to PrPSc in vitro can be facilitated in the presence of iPrP, by using the highly efficient in vitro conversion system termed serial protein misfolding cyclic amplification;and 3) to determine whether iPrP prepared by enrichment or amplification is infectious, by using transmission study in transgenic mice expressing human PrP. The proposed study will improve our understanding of PrPSc formation in the spontaneous prion diseases, and facilitate the development of early diagnostic and therapeutic strategies.

Public Health Relevance

Prion diseases are a group of incurable, transmissible spongiform encephalopathies affecting both animals and humans. The critical molecular event in the pathogenesis of prion diseases, the conversion of a cellular prion protein (PrPC) into its pathological and infectious forms (PrPSc, or prions), remains poorly understood (Prusiner, 1998). The proposed study, exploring the role in the pathogenesis of prion diseases of a PrPSc-like form (termed iPrP), which we recently identified in the normal brain (Yuan et al., 2006), will improve our understanding of the molecular mechanism of PrPSc formation in the spontaneous prion diseases, and facilitate development of early diagnostic and therapeutic strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Xiao, Xiangzhu; Yuan, Jue; Qing, Liuting et al. (2014) Comparative Study of Prions in Iatrogenic and Sporadic Creutzfeldt-Jakob Disease. J Clin Cell Immunol 5:
Pirisinu, Laura; Nonno, Romolo; Esposito, Elena et al. (2013) Small ruminant nor98 prions share biochemical features with human gerstmann-straussler-scheinker disease and variably protease-sensitive prionopathy. PLoS One 8:e66405
Xiao, Xiangzhu; Cali, Ignazio; Dong, Zhiqian et al. (2013) Protease-sensitive prions with 144-bp insertion mutations. Aging (Albany NY) 5:155-73
Yuan, Jue; Zhan, Yi-An; Abskharon, Romany et al. (2013) Recombinant human prion protein inhibits prion propagation in vitro. Sci Rep 3:2911
Xiao, Xiangzhu; Yuan, Jue; Haik, Stephane et al. (2013) Glycoform-selective prion formation in sporadic and familial forms of prion disease. PLoS One 8:e58786
Kudo, Wataru; Lee, Hyun-Pil; Zou, Wen-Quan et al. (2012) Cellular prion protein is essential for oligomeric amyloid-ýý-induced neuronal cell death. Hum Mol Genet 21:1138-44
Mikol, Jacqueline; Deslys, Jean-Philippe; Zou, Wen-Quan et al. (2012) Creutzfeldt-Jakob disease with unusually extensive neuropathology in a child treated with native human growth hormone. Clin Neuropathol 31:127-34
Zou, Roger S; Fujioka, Hisashi; Guo, Jian-Ping et al. (2011) Characterization of spontaneously generated prion-like conformers in cultured cells. Aging (Albany NY) 3:968-84
Gambetti, Pierluigi; Puoti, Gianfranco; Zou, Wen-Quan (2011) Variably protease-sensitive prionopathy: a novel disease of the prion protein. J Mol Neurosci 45:422-4
Vital, A; Laplanche, J-L; Bastard, J-R et al. (2011) A case of Gerstmann-Straussler-Scheinker disease with a novel six octapeptide repeat insertion. Neuropathol Appl Neurobiol 37:554-9

Showing the most recent 10 out of 17 publications