Research

The study by molecular genetic approaches of the cellular mechanisms involved in the formation and propagation of prions

Protein folding is a basic and essential process for life. Inherited alterations in the folding of certain proteins are at the basis of certain genetic diseases such as cystic fibrosis, juvenile emphysema, and certain types of haemophilia (1). Moreover, long fibrillar protein aggregates, designated amyloids, have been implicated in certain diseases such as Parkinson’s, Huntington’s and Alzheimer’s.

Incorrect folding can also be infectious, as is the case of prion-mediated diseases such mad cow disease (BSE), scrapie in sheep, and Creutzfeldt-Jakob in humans (2).

A prion is a protein that can change its “normal” conformation into an alternative one. The latter conformation changes the endogenous function of the protein and is transmitted to other identical molecules; and this eventually results in the formation of oligomeric and fibrillar aggregates. It should be noted that prions are infectious particles devoid of nucleic acids. Hence form the molecular point of view, the mechanism of prion propagation and infectivity is one of the most remarkable discoveries in the last 50 years. This discovery was recognized with the award of the Nobel to Dr Stanley Prusiner (2).

While they are often considered as pathogens, in yeast it was found that prions can have beneficial roles, acting as “molecular switches” in the control of cellular pathways (3-6). Indeed, two basic features of prions allow them to acquire and propagate a new trait or information: (i) the change of conformation that entails the loss and/or gain of a function, and (ii) the structural replication of the prion conformation to the sister molecules. In particular, it has been well established that prions act as genetic elements in yeast transmitting a given trait through generations (3-6).

Thanks to their ability to act as metastable genetic elements, it is possible to consider that prions may be involved in diverse epigenetic mechanisms such as the reversible adaptation of cells to environmental variations (7). In this vein, it is also possible to envisage that prion-like elements could be involved in processes of cell differentiation. It is worth noting that a neural protein that appears to be involved in long-term memory in the marine mollusc Aplysia californica, exhibits prion-like features in the yeast S. cerevisiae (8). This suggests that other proteins with prion-like characteristics could play key roles in memory processes in other animals.

Calnexin is a molecular chaperone involved in several key processes of the endoplasmic reticulum such as protein folding and quality control (9-11). Our laboratory has shown that calnexin is essential for viability in the fission yeast Schizosaccharomyces pombe (12). Nevertheless, recently we have demonstrated that a prion-like element designated [cif] acts as a molecular switch activating a cellular pathway allowing the viability of S. pombe in the absence of calnexin (13). In fact, S. pombe cells can adopt two alternative metastable states: one that is absolutely calnexin dependent (Cdn), and another state that is calnexin independent (Cin). Cells in the Cdn state do not contain the [cif] prion, while induction of this prion renders these cells into the Cin state, i.e. independent of calnexin for viability. Similarly, the transfer of the [cif] prion by conjugation or by protein transformation converts the S. pombe cells from the Cdn state into the Cin state. It is important to note that [cif] is the first described prion that is required for viability of an organism under certain conditions, and the first prion found in S. pombe.

The mechanisms of prion conversion and propagation remain not well defined. Nevertheless, it is well accepted that cellular factors such as molecular chaperones affect the conversion and propagation of prions.

In order to explore and further our understanding of the mechanisms of prion conversion and propagation we use the [cif] prion of Schizosaccharomyces pombe as model system. Specifically, our current research is aimed at understanding the following keys questions:

Given the close similarities between S. pombe and animal cells in terms of protein folding and other basic cellular processes (14), our research should contribute to our understanding of the mechanisms of prion conversion and propagation in mammals. Moreover, our studies should shed light on the roles that prions play as molecular switches.

References :

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(12) Jannatipour M and Rokeach LA (1995). The Schizosaccharomyces pombe homologue of the chaperone calnexin is essential for viability. J.Biol.Chem. 270, 4845-4853.
(13) Collin P, Beauregard PB, Elagöz A, and Rokeach LA (2004). A non chromosomal factor allows viability of Schizosaccharomyces pombe lacking the essential chaperone calnexin. J. Cell Sci. 117, 907-918.
(14) Sipiczki M (2004). Fission Yeast Phylogenesis and Evolution. In : The Molecular Biology of Schizosaccharomyces pombe: Genetics, genomics and beyond. R Egel Ed. Springer Verlag, Berlin-Heidelberg.