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  • Prof.  Albert Taraboulos
Prof Albert Taraboulos
Research Interests
Prions (Prusiner, S.B., Science 1982; 216:136-44) are unusual pathogens that cause a class of invariably fatal neurodegenerations, such as Creutzfeldt-Jakob disease of humans, scrapie of sheep, and bovine spongiform encephalopathy (or mad cow disease).  Prion diseases can be transmitted, inherited, or sporadic.  Prions appear to “replicate” and to transmit their identity to their progeny, without the help of nucleic acids.  Instead, they seem to propagate by refolding a normal cell surface protein, PrPC, into a “prion” conformation called PrPSc, which in turn serves as a template for further conversion.  The mechanistic and cell biological details of this event are still poorly understood.  PrPC is a small (231 aa in the mature protein) glycophospatidyl inositol (GPI)-anchored glycoprotein.  Its functions have not yet been firmly established.  Our research focuses on the cellular metabolism of PrPC and PrPSc in cultured cells.  PrPC is expressed by a variety of cell types.  In contrast, the formation, metabolism, and pathogenesis of PrPSc can only be studied in a few cell types susceptible to prions, such as N2a mouse neuroblastoma and GT1 mouse hypothalamic cell lines.  Prion-infected cells produce both prion infectivity and PrPSc.  
Our studies include:
Prions and lipid “rafts”.  Rafts are microdomains of the membrane that are enriched in cholesterol and in sphingolipids, and that are involved in a wide variety of cellular processes (reviewed in Simons and Ehehalt, J Clin Invest. 2002; 110:597-603).  Both PrP isoforms seem to be attached to rafts via their GPI moiety.  There is evidence that rafts facilitate the formation of PrPSc, and we are trying to understand the mechanisms involved, which may include one or more of the following: (i) rafts target the trafficking of PrP to propitious PrPSc biosynthetic compartments. (ii) they help laterally crowd ‘seed’ PrPSc and ‘substrate’ PrPC, thereby promoting their interaction (crowding could be exacerbated by endocytosis), or (iii) there is a direct interaction of raft cholesterol and SL with PrP, that can lead to PrP destabilization and refolding. 
Prions and proteoglycans.  Proteoglycans, and especially heparan sulfate, have long been associated with the pathology of prion diseases.  We recently found that cell surface heparan sulfates are required for the biogenesis of PrPSc in ScN2a cells, and that they feature as cell-surface receptors for purified prion “rods”.
Folding and misfolding of PrPC.  Since PrP misfolding is potentially toxic, it is very important to understand its folding pathways in the secretory pathway.  We recently found that cyclophilins, which are cis-trans peptidyl-prolyl isomerases, may be involved in PrP folding.  Their inhibitor, cyclosporin A, induces the formation of PrP “aggresomes”.  We are now trying to determine the relevance of this finding for the etiology of a subset of familial prion diseases linked to proline substitutions in PrP.
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