Pathogenesis of Transmissible Spongiform Encephalopathies
Principal Investigator: Pedro Piccardo, MD
Office / Division / Lab: OBRR / DETTD / LBTSEA
Transmissible spongiform encephalopathies (TSEs or prion diseases) are fatal brain diseases of humans and animals. In cattle, TSE is popularly known as "mad cow disease." In most cases of TSE, microscopic examination of the brain finds many small holes called vacuoles, making the tissue look spongy.
In humans, TSE illnesses occur as sporadic (isolated and seemingly random), familial (occurring among family members) or iatrogenic (spread by contaminated medical products or surgical instruments). It is speculated that TSEs occur after a protein called PrPC, normally present in many cells, assumes an abnormal form and accumulates in tissues-mostly in the brain. The abnormal protein is called PrPTSE. When accumulations of PrPTSE are sufficiently large, they form blobs or "plaques" that can be stained by special dyes. Proteins of this kind-not just PrPTSE-are called "amyloid" proteins. Many scientists are convinced that the agent causing TSE is composed solely of PrPTSE.
There is no cure for a TSE, and there is no validated test for TSE and no reliable test that identifies infected humans or animals or animals before onset of clinical illness. Unfortunately, the infectious TSE agent can be present in some tissues of apparently healthy humans and animals for years; those tissues, including blood, have been used to make FDA-regulated medical products to treat serious illnesses and have accidentally infected people treated with those products. Therefore, FDA scientists are trying to understand the basic mechanisms of TSE diseases better and to develop improved strategies for protecting public health.
Although the detection of PrPTSE in samples is valuable for the diagnosis of disease, PrP tests are not very sensitive, so the presence of infectivity in tissue and biologics must be confirmed by special tests that use animal models.
Our research program, in collaboration with academic institutions, investigates TSEs by studying the characteristics of these diseases in humans and in animal models. These studies should improve our understanding of the mechanisms of disease and the role PrPTSE plays in the development of TSEs.
This new knowledge will help scientists develop practical tools to improve the early diagnosis of TSEs and might also help to develop effective therapies by preventing the transformation of PrPC into PrPTSE.
Transmissible spongiform encephalopathies (TSEs or prion diseases) are fatal diseases of humans and animals. In humans, TSEs occur as sporadic, familial or iatrogenic illnesses. TSEs are associated with the conversion of a normal host-encoded protein (PrPC) into a misfolded form (PrPTSE) that accumulates in the brain and-less strikingly-in other organs. A prevailing hypothesis is that the infectious agents of TSEs are composed solely of PrPTtse.
There is no cure, prevention (except by avoiding contact with the infectious agent) or validated ante-mortem diagnostic test for TSEs. To protect public health, fundamental questions about basic mechanisms of disease and the nature of the infectious agent must be clarified.
The TSE agents pose a major regulatory problem for FDA, which shares with industry the responsibility for ensuring the safety of biologic products. The problem is that some biologic products are manufactured with tissues obtained from human donors or from animals, and there are no validated methods to identify those relatively few TSE-infected individuals or animals during the long period when they exhibit no signs of illness; but we know that some of their tissues may already be dangerous for users of the products.
Currently, the "gold standard" methods for detecting TSE infectivity in tissues and in final biologic products require transmission of disease to susceptible animals, an expensive and time-consuming assay that is not feasible for screening human donors or animals.
Our research program, in collaboration with academia, investigates the pathogenesis of TSEs by characterizing familial cases of TSE with unusual clinical and pathologic presentations and by studying experimental animal models of TSEs. Studying novel genetically engineered (transgenic) mice, we determined that noninfectious aggregates of PrPC severely damage synapses. This finding suggests that TSEs and some non-transmissible neurodegenerative diseases also marked by misfolded amyloid proteins in the brain might share common pathogenic mechanisms. In another line of transgenic mice, we found that formation of PrP amyloid might not necessarily provide a reliable marker of TSE infectivity.
These studies improve basic understanding of pathogenic mechanisms of TSEs at a molecular level-including causes of neuronal death and relationship between the accumulation of abnormal protein and the infectious TSE agents-while providing practical tools for better diagnosis and possible effective therapies.
EMBO J 2013 Mar 6;32(5):756-69
Post-translational changes to PrP alter transmissible spongiform encephalopathy strain properties.
Cancellotti E, Mahal SP, Somerville R, Diack A, Brown D, Piccardo P, Weissmann C, Manson JC
J Comp Pathol 2012 Jul;147(1):84-93
Squirrel monkeys (Saimiri sciureus) infected with the agent of bovine spongiform encephalopathy develop tau pathology.
Piccardo P, Cervenak J, Yakovleva O, Gregori L, Pomeroy K, Cook A, Muhammad FS, Seuberlich T, Cervenakova L, Asher DM
J Gen Virol 2012 May;93(Pt 5):1132-40
Bovine PrP expression levels in transgenic mice influence transmission characteristics of atypical bovine spongiform encephalopathy.
Wilson R, Hart P, Piccardo P, Hunter N, Casalone C, Baron T, Barron RM
PLoS One 2012;7(2):e32382
Allelic origin of protease-sensitive and protease-resistant prion protein isoforms in Gerstmann-Sträussler-Scheinker disease with the P102L mutation.
Monaco S, Fiorini M, Farinazzo A, Ferrari S, Gelati M, Piccardo P, Zanusso G, Ghetti B
Brain Pathol 2012 Jan;22(1):58-66
Mechanism of PrP-amyloid formation in mice without transmissible spongiform encephalopathy.
Jeffrey M, McGovern G, Chambers EV, King D, González L, Manson JC, Ghetti B, Piccardo P, M Barron R
Emerg Infect Dis 2011 Dec;17(12):2262-9
Candidate cell substrates, vaccine production, and transmissible spongiform encephalopathies.
Piccardo P, Cervenakova L, Vasilyeva I, Yakovleva O, Bacik I, Cervenak J, McKenzie C, Kurillova L, Gregori L, Pomeroy K, Asher DM
J Biol Chem 2011 Sep 23;286(38):33489-500
Prion Protein Interacts with BACE1 Protein and Differentially Regulates Its Activity toward Wild Type and Swedish Mutant Amyloid Precursor Protein.
Griffiths HH, Whitehouse IJ, Baybutt H, Brown D, Kellett KA, Jackson CD, Turner AJ, Piccardo P, Manson JC, Hooper NM
J Virol 2011 Feb;85(3):1174-81
Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy following passage in sheep.
Plinston C, Hart P, Chong A, Hunter N, Foster J, Piccardo P, Manson JC, Barron RM
Transfusion 2011 Aug;51(8):1755-68
Fukuoka-1 strain of transmissible spongiform encephalopathy agent infects murine bone marrow-derived cells with features of mesenchymal stem cells.
Cervenakova L, Akimov S, Vasilyeva I, Yakovleva O, McKenzie C, Cervenak J, Piccardo P, Asher DM
J Virol 2010 Apr;84(7):3464-75
Glycosylation of PrPC determines timing of neuroinvasion and targeting in the brain following transmissible spongiform encephalopathies infection by a peripheral route.
Cancellotti E, Bradford BM, Tuzi NL, Hickey RD, Brown D, Brown KL, Barron RM, Kisielewski D, Piccardo P, Manson JC
Brain Path 2010 Mar;20(2):419-30
PET of brain prion protein amyloid in Gerstmann-Sträussler-Scheinker disease.
Kepe V, Ghetti B, Farlow MR, Bresjanac M, Miller K, Huang SC, Wong KP, Murrell JR, Piccardo P, Epperson F, Repovs G, Smid LM, Petric A, Siddarth P, Liu J, Satyamurthy N, Small GW, Barrio JR.
J Neurosci 2008 Dec 3;28(49):13258-67
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
Proteasomal inhibition induced by anganeseethylene-bis-dithiocarbamate: Relevance to parkinson's disease.
Zhou Y, Shie FS, Piccardo P, Montine TJ, Zhang J