The prion protein preference of sporadic Creutzfeldt-Jakob disease subtypes

From the Department of Pathology.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2012; 287(43):36465-72. DOI: 10.1074/jbc.M112.368803
Source: PubMed


Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes.

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    ABSTRACT: Prion diseases, traditionally referred to as transmissible spongiform encephalopathies (TSE), are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of mammalian species, manifesting as scrapie in sheep, bovine spongiform encephalopathy (BSE, or ‘mad-cow’ disease) in cattle, and Creutzfeldt-Jakob disease (CJD), Gerstmann-Strussler-Scheinker syndrome(GSS), Fatal familial insomnia (FFI) and Kulu in humans, etc. These neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrPC) into insoluble abnormally folded infectious prions (PrPSc). The hydrophobic region PrP 109–136 controls the formation into diseased prions: the normal PrP(113–120) AGAAAAGApalindrome is an inhibitor/blocker of prion diseases (Mol Cell Neurosci 15: 66–78), and the highly conserved Glycine-xxx-Glycine motif PrP(119–131) can inhibit the formation of infectious prion proteins in cells (J Biol Chem 285: 20213-20223). This paper gives detailed reviews on the PrP(109–136) region and presents the studies of its 3D structures and structural dynamics.
    Acta Biochimica et Biophysica Sinica 02/2013; · 2.19 Impact Factor
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    ABSTRACT: The polymorphism at codon 129 of the prion protein gene (PRNP) is a major risk factor for Creutzfeldt-Jakob disease (CJD). Several authors reported neuropathological and clinical overlapping between CJD and Alzheimer's disease (AD), with a few association studies generating conflicting results. To investigate the distribution of this polymorphism in AD, we selected 58 patients with probable AD and 73 controls from a Brazilian population. There was no association between the PRNP polymorphism at codon 129 and AD. Our meta-analysis (performed using Alzgene; ) along with previous studies conducted in Brazil demonstrated a negative association.
    Neurological Research 02/2014; 36(9):1743132814Y0000000332. DOI:10.1179/1743132814Y.0000000332 · 1.44 Impact Factor