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 1-helixes to 2-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.
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.
|Orrú, Christina D; Yuan, Jue; Appleby, Brian S et al. (2017) Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med 9:|
|Xiao, Xiangzhu; Shen, Pingping; Wang, Zerui et al. (2017) Characterization of physiochemical properties of caveolin-1 from normal and prion-infected human brains. Oncotarget 8:53888-53898|
|Das, Alvin S; Zou, Wen-Quan (2016) Prions: Beyond a Single Protein. Clin Microbiol Rev 29:633-58|
|Zhan, Yi-An; Abskharon, Romany; Li, Yu et al. (2016) Quiescin-sulfhydryl oxidase inhibits prion formation in vitro. Aging (Albany NY) 8:3419-3429|
|Pirisinu, Laura; Di Bari, Michele A; D'Agostino, Claudia et al. (2016) Gerstmann-Sträussler-Scheinker disease subtypes efficiently transmit in bank voles as genuine prion diseases. Sci Rep 6:20443|
|Cali, Ignazio; Miller, Cathleen J; Parisi, Joseph E et al. (2015) Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone. Acta Neuropathol Commun 3:37|
|Xiao, Xiangzhu; Cali, Ignazio; Yuan, Jue et al. (2015) Synthetic A? peptides acquire prion-like properties in the brain. Oncotarget 6:642-50|
|Zhang, Bo; Cowden, Daniel; Zhang, Fan et al. (2015) Prion Protein Protects against Renal Ischemia/Reperfusion Injury. PLoS One 10:e0136923|
|Orrú, Christina D; Groveman, Bradley R; Raymond, Lynne D et al. (2015) Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains. PLoS Pathog 11:e1004983|
|Notari, Silvio; Xiao, Xiangzhu; Espinosa, Juan Carlos et al. (2014) Transmission characteristics of variably protease-sensitive prionopathy. Emerg Infect Dis 20:2006-14|
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