Pathogenesis of Transmissible Spongiform Encephalopathies

Principal Investigator: Pedro Piccardo, MD
Office / Division / Lab: OBRR / DETTD / LBPUA

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Overview

Public Health Issue: Blood and tissues of humans and animals are used to manufacture a variety of biological products. Both have transmitted transmissible spongiform encephalopathies (TSEs or prion diseases) to recipients of products. It is difficult to identify infected persons and animals during the long asymptomatic incubation periods of TSEs (sometimes lasting many years) but their blood and tissues nonetheless may transmit infection.

Regulatory Contribution: The presence in tissues of abnormal isoforms of the prion protein (PrP) is widely and successfully used to diagnose TSEs. However, abnormal PrP is not always detected in infected tissues. Furthermore, some abnormal forms of PrP are not associated with infectivity. The situation must be clarified before FDA can rely on tests of abnormal PrP as a reliable surrogate for bioassays of infectivity assays which are cumbersome, expensive and require use of animals kept under observation for months or even years.

Research Approach: Analysis of transgenic mouse models that express wild-type and mutant prion proteins are used to determine the correlation between abnormal prion protein and infectivity. Transgenic technology is used to investigate the function of cellular prion protein. Several immunodetection techniques, and the use of transgenic mice and non-human primates as bioassays, are used for the detection of TSE agents in studying the potential of several cell substrates (used in the manufacture of vaccines) to support the growth of TSE infectious agents.

Mission Relevance & Outcomes: Improvements in the detection of abnormal PrP and better bioassays for infectivity will become increasingly important for evaluating research tests recently reported to offer antemortem diagnoses of humans and animals incubating TSEs and eventually for possible screening of blood donors.

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Publications

J Neurosci 2008 Dec 3;28(49):13258-13267
Aggregated, Wild-Type Prion Protein Causes Neurological Dysfunction and Synaptic Abnormalities.
Chiesa R, Piccardo P, Biasini E, Ghetti B, Harris DA

PLoS Biol 2008 Apr 15;6(4):e100
Host PrP glycosylation: a major factor determining the outcome of prion infection.
Tuzi NL, Cancellotti E, Baybutt H, Blackford L, Bradford B, Plinston C, Coghill A, Hart P, Piccardo P, Barron RM, Manson JC

EMBO J 2007 Jun 6;26(11):2777-85
Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice.
Li A, Piccardo P, Barmada SJ, Ghetti B, Harris DA

Proc Natl Acad Sci U S A 2007 Mar 13;104(11):4712-7
Accumulation of prion protein in the brain that is not associated with transmissible disease.
Piccardo P, Manson JC, King D, Ghetti B, Barron RM

J Histochem Cytochem 2006 Jan;54(1):97-107
Computerized Morphometric Analysis of Pathological Prion Protein Deposition in Scrapie-Infected Hamster Brain.
Maximova OA, Taffs RE, Pomeroy KL, Piccardo P, Asher DM.

J Neurosci 2005 Mar 30;25(13):3469-77
Neurodegenerative illness in transgenic mice expressing a transmembrane form of the prion protein.
Stewart RS, Piccardo P, Ghetti B, Harris DA.

Proc Natl Acad Sci U S A 2005 Jan 4;102(1):238-43
Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease.
Chiesa R, Piccardo P, Dossena S, Nowoslawski L, Roth KA, Ghetti B, Harris DA.

Neurobiol Dis 2004 Aug;16(3):527-37
GFP-tagged prion protein is correctly localized and functionally active in the brains of transgenic mice.
Barmada S, Piccardo P, Yamaguchi K, Ghetti B, Harris DA.

Brain Path 2004 Apr;14(2):137-47
Early-onset dementia with Lewy bodies.
Takao M, Ghetti B, Yoshida H, Piccardo P, Narain Y, Murrell JR, Vidal R, Glazier BS, Jakes R, Tsutsui M, Spillantini MG, Crowther RA, Goedert M, Koto A.

Neuroscience 2004;128(2):281-91
Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: Relevance to parkinson's disease. 
Zhou Y, Shie FS, Piccardo P, Montine TJ, Zhang J.