Autophagy in the limelight

Tor Erik Rusten
Autophagy is the process by which all eukaryotic cells recycle cytoplasm and dispose of excess or defective organelles (see box 1). This process has entered the research limelight during 2003-2004 due to the recent findings that autophagy is important for protection against neurodegenerative disease, cancer, and infections [1]. Owing to the pioneering work of Per Ottar Seglen and his group on autophagy in rat liver, the Norwegian Radium Hospital has a strong research tradition in the field of autophagy. Taking advantage of recent advances in molecular biology and genetcis, the Norwegian Radium Hospital has the opportunity to stay in the forefront of this research.
Yeast genetics led to a breakthrough in autophagy research
The use of yeast genetics in studying autophagy has allowed the identification of the core machinery of molecules involved in forming the autophagic membranes[2]. Importantly, two molecules of this molecular machinery, termed Atg5 and Atg8, serve as molecular markers for the autophagic vesicles. It was later shown that homologues of these molecules also label these structures in mice and plants. It is fair to say that the ease of use of these markers is directly responsible for the breakthrough in autophagic research observed in 2003-2004.

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Using genetics in fruitflies provides a good picture of physiological pathways in mammals
Genetics provide a means to search for novel molecular components that control a biological process such as autophagy, and to establish the importance of this process for viability, physiology and disease. The use of genetics in yeast took advantage of the first point, finding the core components of the autophagic machinery. It is reasonable to believe that the core components are largely conserved. The regulation and functions of autophagy are, however, much more complex in higher animals. This called for use of higher animals in autophagic research that reproduce better what is going on in humans.

The fruitfly, Drosophila melanogaster, provides a favoured model organism for molecular genetic research, and is increasingly used to study basic biological principles of disease, such as neurodegeneration and cancer. The popularity of Drosophila as a model system lies in its well-characterized genetics and the fact that it closely emulates biological processes in mammals. In a recent survey of the genome, 197 human disease genes out of 287 can be found in Drosophila, and even those that do not can produce very similar symptoms when expressed in flies.

In our studies we established transgenic flies that can be used to study the regulation and importance of autophagy in a range of processes and disease [3]. We showed that two signalling pathways previously shown by Seglen and others to regulate autophagy in mammalian cell culture also applied to Drosophila. This is important, since it demonstrates that regulatory pathways present in Drosophila and mammals (and not present in yeast) provide a similar regulatory control of the process. Furthermore, our studies provided insight into how these regulatory pathways are interconnected during normal development of an animal.

These studies opens up the use of Drosophila to 1) search for novel regulatory components of the process that apply also for humans, and 2) address the importance of autophagy in normal development, cell death and disease. We are currently pursuing these goals.
  1. Shintani, T. and D.J. Klionsky, Autophagy in health and disease: a double-edged sword. Science, 2004. 306(5698): p. 990-5.
  2. Noda, T., K. Suzuki, and Y. Ohsumi, Yeast autophagosomes: de novo formation of a membrane structure. Trends Cell Biol, 2002. 12(5): p. 231-5.
  3. Rusten, T.E., et al., Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev Cell, 2004. 7(2): p. 179-92.
 
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