Báo cáo khoa học: Prions and prion diseases docx

MINIREVIEW SERIES Prions and prion diseases Michael Beekes Robert Koch-Institut (P24 – Transmissible Spongiforme Enzephalopathien), Berlin, Germany 1 The epidemic of bovine spongiform encephalopathy (BSE), or ‘mad cow disease’, and the subsequent emer- gence of a new variant of Creutzfeldt–Jakob disease (vCJD) in humans, has directed great political and sci- entific attention to a family of related neurodegenera- tive protein-misfolding diseases, collectively known as transmissible spongiform encephalopathies (TSEs) or prion diseases. TSEs cause a progressive and eventu- ally fatal degeneration of the central nervous system (CNS). All members of this group of diseases are char- acterized by the deposition, in the CNS, of a patholo- gical form of the prion protein (PrP) with an aberrant folding and ⁄ or aggregation structure (PrP TSE ). The puzzling properties of scrapie- and other TSE agents have caused a vivid controversial debate about the molecular nature and biochemical composition of these pathogens for many years. According to the pri- on hypothesis, the causative agents of TSEs are protei- naceous infectious particles (‘prions’), which are composed essentially – if not entirely – of misfolded prion protein, referred to as PrP Sc . The formation and amplification of ‘infectious PrP Sc ’ is assumed to follow a mechanism of seeded aggregation, but for a long time it could not be shown that misfolded proteinase K-resistant prion protein (PrP res ) generated ex vivo is associated with pathogenic infectivity (i.e. the ability to induce a TSE in vivo). However, substantial advances on the in vitro generation of infectious scrapie prions by growing amyloid fibrils from bacterially expressed recombinant PrP, or by replicating PrP res using protein misfolding cyclic amplification (PMCA), have been achieved recently. As reviewed by Ilia Baskakov, this added new pieces of evidence to the puzzle of findings corroborating the prion hypothesis. Prions underlie the transmission of TSEs in the ani- mal kingdom, between humans, and from animals to humans. Once prions have entered a host organism, they spread from the site of invasion to the brain, their ultimate target organ. Contact with prions can occur under various conditions, but TSEs such as scrapie, BSE, chronic wasting disease (CWD) and vCJD are assumed to originate from peroral prion infections in the majority of cases. The potential risks that prions pose to public health, and the identification of the oral route as a key pathway for their transmission, have emphasized the need for systematic studies on the pathogenesis of perorally acquired TSEs. Michael Beekes and Patricia McBride summarize the current knowledge on the spread of scrapie, CWD, BSE and vCJD through the body in naturally affected hosts and in animals experimentally challenged via the aliment- ary tract. Although this knowledge has substantially expanded during the past few years, the molecular mechanisms of the spread of prions in the nervous sys- tem remain elusive. A better understanding of these mechanisms may help to identify approaches for inhib- iting the propagation of infection in the CNS where prions confer the neuopathological damage that even- tually leads to clinical disease. Apart from the deposition of PrP TSE , features of CNS neuropathology in scrapie and other TSEs often include vacuolar (or ‘spongiform’) change, glial activa- tion, synaptic degeneration and loss of neurons. The exact molecular pathways and mechanisms through which pathological prion protein or its misfolding intermediates are involved in the production of neuro- pathological changes, and eventually fatal cerebrospi- nal dysfunction, are as yet unknown. Jo ¨ rg Tatzelt and Hermann Scha ¨ tzl discuss selected aspects of the molecular basis of cerebral neurodegeneration in prion diseases in the third part of this minireview series. To date, no effective prophylactics or therapeutics against TSEs are available. This emphasizes the import- ance of further research on prion diseases, not least because the ongoing lack of possibilities for medical inter- vention is strongly reminiscent to the situation known from other neurodegenerative protein-misfolding disor- ders, such as Alzheimer’s disease or Parkinson’s disease. Michael Beekes is a biochemist and received his diploma and PhD degree from the Free University of Berlin, where he currently has a teaching assignment as a private lecturer. He has been working in the field of prion diseases since 1990 and is leader of the project ‘Transmissible Spongiform Encephalopathies’ at the Robert-Koch-Institute in Berlin. His main research interests are the pathophysiology of prion spread through the body, TSE diagnostics, the molecular basis of prion strain diversity and the inactivation of TSE agents. doi:10.1111/j.1742-4658.2006.05629.x FEBS Journal 274 (2007) 575 ª 2007 The Author Journal compilation ª 2007 FEBS 575 . of findings corroborating the prion hypothesis. Prions underlie the transmission of TSEs in the ani- mal kingdom, between humans, and from animals to humans. Once prions have entered a host organism, they. MINIREVIEW SERIES Prions and prion diseases Michael Beekes Robert Koch-Institut (P24 – Transmissible Spongiforme Enzephalopathien),. protei- naceous infectious particles ( prions ), which are composed essentially – if not entirely – of misfolded prion protein, referred to as PrP Sc . The formation and amplification of ‘infectious