Abstract
The second issue of Prion, which we are happily presenting to the reader, is further emphasizing our general strategy of covering prions and related phenomena in different experimental settings, with the attention to both biological roles and clinical applications.
We happily present the second issue of Prion that further emphasizes our general strategy of covering prions and related phenomena in different experimental settings, with attention to both biological roles and clinical applications.
Manifesting this integrative approach, this issue begins with the review paper by A. Steele, S. Lindquist and A. Aguzzi, which provides a comprehensive coverage of current literature aimed at elucidation of the normal function of the mammalian prion protein (PrP). Even though our understanding of PrP-induced pathology is still at the rudimentary stages, it would be fair to say that we understand biological functions of PrP even less. Steele and coauthors are making a brave attempt at filling up this gap.
This issue also contains the meeting report of the recent Jacques Monod Conference on Protein Misfolding and Aggregation in Ageing and Diseases by M. Tuite and R. Melki. (A minireview series written by the participants of this conference was included in the first issue.) Four research papers follow, providing interesting new data on various aspects of prion biology and protein aggregation in both mammalian and yeast systems, from detection of disease-associated prions in various mammalian tissues (G. Barnard et al.), to characterization of polyglutamine (Y. Wang et al.) and polyasparagine (T. Peters and M. Huang) aggregates in yeast, and to combinatorial lethality of the prion and mutant derivatives of the yeast release factors (D. Kiktev et al.)
Also included in this issue are three more reviews that I'd like to introduce in a little more detail. These are selected chapters from the new book which is about to be published by Landes Bioscience (Chernoff Y, ed. Protein-Based Inheritance, Austin: Landes Bioscience, 2007). This book covers a long-neglected biology topic, which only recently has come back into the spotlight. Until the genetic role of DNA was firmly established, many researchers suspected that proteins rather than nucleic acids could be carriers of heritable information. These models were completely forgotten with the triumphal march of a double helix and development of a central dogma postulating that informational flow occurs strictly in the direction from DNA through RNA to protein, making it seemingly impossible for the proteins to possess a coding potential. Proteins were downgraded to the role of simple perpetuators and executors of DNA orders. While it was certainly recognized that protein “serfs” are indispensable for the well-being of their powerful nucleic acid “lords”, the thought of a protein occupying a key position in the hereditary hierarchy was as unthinkable in modern molecular genetics as were peasants' aspirations to the throne in medieval Europe.
As it frequently occurs in science, data that could not be explained within the framework of a “nucleic acid only” model of heredity existed for years waiting for the proper moment to resurface. Attention to these non-conventional phenomena was attracted by studying the transmissible spongiform encephalopathies (TSEs), later termed “prion diseases”. Accumulated results led to the revolutionary model proposing that a TSE infectious agent (prion) is composed of the wrongly shaped protein, capable of converting the normal protein of the same amino acid sequence into a prion shape. Mammalian prion diseases were covered in great detail in some recent books (for example, Prusiner S, ed. Prion Biology and Diseases, Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2004, and Telling G, ed. Prions and Prion Diseases: Current Perspectives, Norwich, UK: Horizon Scientific Press, 2004). Although transmission of mammalian prions from one organism to another represents infection rather than inheritance, the ability of a protein to act as an information carrier, postulated in the prion model of TSEs, certainly paved the way for acceptance of such a role in heredity for at least some proteins as well.
Extension of the prion model to some yeast non-Mendelian elements was initiated by R. Wickner in 1994 and confirmed by further research in various labs. Recent advances leave no doubts that patterns of the fungal prions are controlled and reproduced exclusively at the protein level. In principle, a prion mechanism of inheritance does not contradict a central dogma, as DNA is still needed for initial protein production. However, prion transmission in generations clearly shows that changes occurring at the protein level can become reproducible and heritable without any corresponding change occurring in DNA sequences. Heritable prions essentially meet all the criteria of non-Mendelian genes that were in use during the classic genetics era.
Taken together, data reviewed in our new book prove beyond reasonable doubt that proteins and multiprotein complexes are able to control heritable traits, and that at least in some examples, this control occurs in a template-like fashion, so that new structures strictly reproduce patterns of pre-existing structures that were not specifically coded in DNA. Thus, protein-based inheritance has left the area of speculations and emerged as a new topic amenable to high-quality experimental analysis. Nucleic acid lords will no longer be capable of disregarding the contributions of their protein serfs to the overall heritable composition of the cell and organism. Moreover, connections between the mechanisms of protein-based heritable phenomena and some important diseases (such as Alzheimer disease and other disorders related to amyloid formation) make it probable that protein-based inheritance will attract even more attention in near future.
The chapters of Protein-Based Inheritance offered in this issue focus on the parallels between mammalian and fungal prions, genesis of the yeast prion concept and descriptions of specific fungal prions. Future issues of Prion will contain additional chapters of the book, all of which are available at http://www.landesbioscience.com.