Article

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

ABSTRACT

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 (PrPC). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrPC substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrPC 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 PrPC substrate was sourced, thus indicating that nuances in PrPC 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.
    Full-text · Article · Feb 2013 · Acta Biochimica et Biophysica Sinica
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    [Show abstract] [Hide abstract]
    ABSTRACT: Prion diseases, traditionally referred to as transmissible spongiform encephalopathies, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of mammalian species, manifesting as scrapie in sheep, bovine spongiform encephalopathy (or ‘mad-cow’ disease) in cattle, and Creutzfeldt–Jakob disease, Gerstmann–Strussler–Scheinker syndrome, 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 of diseased prions: the normal PrP(113-120) AGAAAAGA palindrome is an inhibitor/blocker of prion diseases and the highly conserved glycine-xxx-glycine motif PrP(119-131) can inhibit the formation of infectious prion proteins in cells. This article gives detailed reviews on the PrP(109-136) region and presents the studies of its three-dimensional structures and structural dynamics.
    Full-text · Article · May 2013 · Acta Biochimica et Biophysica Sinica
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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; http://www.alzgene.org ) along with previous studies conducted in Brazil demonstrated a negative association.
    No preview · Article · Feb 2014 · Neurological Research
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