Clin Lab Med. 2003 Mar;23(1):175-86. A murine model of a familial prion disease.
Harris DA, Chiesa R, Drisaldi B, Quaglio E, Migheli A, Piccardo P, Ghetti B.
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA. dharriellbio.wustl.edu
We have produced a mouse model of a familial prion disorder by introduction of a transgene that encodes the moPrP homolog of a nine-octapeptide insertional mutant associated with an inherited form of CJD in humans. These mice develop progressive neurologic symptoms, display neuropathologic changes, and accumulate a form of mutant PrP in their brains and peripheral tissues that displays some of the biochemical properties of PrPSc. These mice have been extremely valuable for analyzing the cellular and biochemical mechanisms involved in inherited prion disorders and correlating the appearance of the PrPSc-like form with clinical and neuropathologic findings. Because the mutant protein in the mice is highly neurotoxic but appears to lack infectivity, further analysis of its properties promises to shed new light on the molecular distinction between pathogenic and infectious forms of PrP.
PMID:_12733431 [PubMed - in process]
Clin Lab Med. 2003 Mar;23(1):187-208. Therapeutic approaches to prion diseases.
Rossi G, Salmona M, Forloni G, Bugiani O, Tagliavini F.
Division of Neuropathology and Neurology, Instituto Nazionale Neurologico Carlo Besta, Via Celoria 11, 20133 Milano, Italy.
Prion diseases are unique in that they comprise sporadic, genetic, and iatrogenically or environmentally acquired forms. When disease is acquired by peripheral route, neuroinvasion occurs via at least two different neural pathways (vague and splanchnic nerves) and is usually preceded by prion propagation in secondary lymphoid organs. Conversely, in the other etiologic forms, PrPSc formation occurs within, and is apparently limited to, the CNS. Longitudinal studies on experimental scrapie indicate that substantial neuropathologic changes (i.e., glial activation and nerve cell degeneration) already are present before the onset of symptoms and are topographically related to PrPSc deposits. Accordingly, any effective intervention should start during the preclinical stage of disease, and be aimed at preventing neuroinvasion or PrPSc propagation in the CNS. Unfortunately, no tests are available currently to detect presymptomatic individuals, except for carriers of pathogenic mutations of the PRNP gene. Inhibition of PrPSc formation can be achieved through (1) abrogation of PrPC synthesis or prevention of its transport to the cell surface; (2) stabilization of the PrPC structure to make its conformational change unfavorable; (3) sequestration of PrPSc; (4) reversion of PrPSc to a protease-sensitive form; or (5) interference with the interaction between PrPC, PrPSc, and other macromolecules that feature in the conversion process. The compounds that have some effectiveness in in vitro, cell culture, or animal models of prion disease seem to operate through one of these mechanisms (see Table 1); however, even the most effective drugs only work when administered at the time of infection or very short thereafter, and these conditions are incurable at present. The heterogeneity and complexity of the etiopathogenesis of prion diseases suggest that various strategies and a combination of several compounds with different modes of actions are likely necessary for prevention and treatment. Major efforts should be focused on the development of preclinical diagnostic tests in conjunction with immunization strategies for diseases acquired by peripheral route and identification of more effective compounds for the other etiological forms.
PMID:_12733432 [PubMed - in process]
Clin Lab Med. 2003 Mar;23(1):209-25. Three-dimensional structures of the prion protein and its doppel.
Riek R, Luhrs T.
Structural Biology Laboratory, Salk Institute, 10010 North Torry Pines Road, La Jolla, CA 92037, USA. riebl.salk.edu
This article discussed the implications of the structures of PrP and Dpl--with their unusual folds containing N-terminal flexible tails and C-terminal globular domains--to the physiologic functions of PrPC and Dpl, and investigations of a possible structural basis of familial human TSEs. Further relations between TSEs and the PrP structure would include the species barrier of TSEs (which seems to be associated with species-specific structural characteristics of PrPC [25,39,67]), and the conformational transition from PrPC to PrPSc using, for example, molecular dynamic simulations [68,69]. Due to the lack of knowledge on physiologic functions of PrPC, however, and the remaining uncertainty about the exact role of the PrP in TSE pathology, it appears that most or all of the physiologically relevant structure-function correlations of PrPC have yet to be identified.
PMID:_12733433 [PubMed - in process]
Clin Lab Med. 2003 Mar;23(1):227-47. In vitro conversion of normal prion protein into pathologic isoforms.
Bossers A, Rigter A, de Vries R, Smits MA.
Central Institute for Animal Disease Control (CIDC-Lelystad), P.O. Box 2004, 8203 AA Lelystad, The Netherlands. a.bosserd.dlo.nl
The in vitro conversion techniques in cell-free and cell culture systems have provided tools to adequately study the underlying mechanism of TSEs, namely PrP conversion. These systems also have provided tools that make it easier to study the interspecies and intraspecies transmissibilities of TSEs. Finally, these systems also may assist in the discovery of TSE therapeutic strategies and in the development of extremely sensitive TSE detection techniques. In vivo TSE transmission studies are limited to (transgenic) animals (mostly mice). Although the cell culture systems also are restricted in their species-range (mostly mouse), the currently used cell-free systems. Allow studying almost all possible species barriers (including the potential transmission of various TSEs to humans). One advantage of the cell culture systems, however, is that they generate do novo TSE infectivity. Studies using cell cultures also take into account several cofactors in addition to PrP that might be involved in replication the TSE agent. Although the in vitro systems provide accurate tools to study TSE agent parameters, they mainly or only focus on the molecular processes of PrP conversion. Other factors (i.e., host genetic factors [99]) that, for example, determine the differential uptake of the TSE agent from the environment, might play an additional role in determining the susceptibility of hosts for TSEs and on the transmission of the disease among individuals.
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