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 stru
Trang 1M I N I R E V I E W S E R I E S
Prions and prion diseases
Michael Beekes
Robert Koch-Institut (P24 – Transmissible Spongiforme Enzephalopathien), Berlin, Germany
1The 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, collecneurodegenera-tively 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 (PrPTSE)
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 PrPSc The formation and
amplification of ‘infectious PrPSc’ 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 (PrPres) 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 PrPresusing 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 aniani-mals 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 PrPTSE, 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