Self-eating keeps us healthy
Our cells eat themselves so that we can stay healthy. A detailed understanding of ‘autophagy’, our cells’ waste management system, may be the key to preventing diseases and extending our lives.
Without ALFY our cells would not be able to clear out their own waste. The consequence could be cancer and dementia. Illustration: Gunnar F. Lothe, UiO.
Cellular waste management system
Our cells contain many different kinds of waste, for example damaged or old organelles. If these are not removed and broken down by autophagy the cell might die, possibly resulting in cancer and dementia.
“We can envisage the cell as a busy town,” says Professor Anne Simonsen. She is a professor and group leader at the Institute of Basic Medical Sciences.
“For the town to function optimally it needs to efficiently get rid of waste, to recycle it into new building material and use it for energy production.”
Professor Simonsen and her research group have previously shown that autophagy is important to prevent misfolded proteins from clumping. An accumulation of this kind can lead to Alzheimer’s disease as well as illnesses such as Parkinson’s disease and Huntington’s disease. Researchers have identified several proteins that can bind to such misfolded disease-associated proteins and label them for breakdown through autophagy, which is necessary for maintaining cell health. Their most recent findings enhance our understanding of this part of the autophagy process, and might prove significant for developing medication against dementia.
Reversing cancer and dementia?
“We have previously shown that the ALFY protein is important in the process, but until now we have not understood exactly why,” says Professor Simonsen.
In their most recent paper, the research group shows that the protein ALFY is necessary for initiating the autophagy process. If ALFY is removed, the autophagy membrane will not be recruited. As a consequence, misfolded and clumped proteins will not be removed by autophagy, resulting in the death of nerve cells and dementia. Experiments on the fruit fly Drosophila have revealed that these flies also get dementia if their version of ALFY is removed. Additionally, it has been shown that increased levels of ALFY in these flies can prevent the accumulation of misfolded proteins.
Anne Simonsen and her group conduct research on the tiny yet crucial details that may contribute to reversing cancer and dementia. From left: Gunnveig Toft Bjørndal, Petter Holland, Aleksander Aas, Kristiane Søreng, Christian Bindesbøll, Anne Simonsen, Serhiy Pankiv, Benan John Mathai, Pauline Isakson, Alf Håkon Lystad. Photo: Gunnar F. Lothe, UiO.
“We hope our studies can help enhance our understanding of the cellular processes that cause cancer and dementia, and that in the long term we will be able to develop medicines that may prevent or even reverse these diseases, possibly by increasing the production or the effect of ALFY,” Professor Simonsen tells us.
Recycling by self-eating
The word autophagy is derived from Greek and means self-eating. A common explanation of the cells’ waste management system is that our cells eat themselves. Simply put, this process implies that the cell breaks down its own waste and uses the remains as new building material. A membrane closes around the waste in the cell and forms a unit that is carried to the cell’s waste station where it is broken down. The remaining products from this decomposition are recycled as building material or utilized in energy production for the cell.
The self-eating process is both normal and necessary, and occurs in all our cells all the time.
Extending our lives
The recycling of material that takes place through autophagy contributes in prolonging the lifetime of the cells. Professor Simonsen and her research group have previously shown that a higher level of autophagy can also extend the life of an organism, in this case the fruit fly Drosophila.
“We know that autophagy is initiated and increased by hunger, and there are grounds to believe that increased autophagy is important for the life-extending effect of so-called ‘caloric restriction’ and ‘intermittent fasting’, which are key factors of the popular 5:2 diet,” Professor Simonsen says.
This is primarily explained by the fact that the clean-up provided by autophagy protects us from cancer and other lifestyle diseases.
Too much can be harmful
If it is true that a lack of autophagy cause disease, why can we not just accelerate the autophagy process?
“Studies have shown that in some cases, too much autophagy can be harmful, for example for certain types and stages of cancer,” Professor Simonsen explains.
“We need to understand the molecular mechanisms involved in the various forms of autophagy in different types of cells in order to manipulate autophagy therapeutically. Our research therefore focuses on the basic questions of autophagy: How is the membrane formed? How is the waste recognized? How is the process regulated?”
In order to develop an effective medicine, the researchers are dependent on as detailed knowledge as possible, and the group is currently working on understanding how ALFY is regulated.
Lystad AH, Ichimura Y, Takagi K, Yang Y, Pankiv S, Kanegae Y, Kageyama S, Suzuki M, Saito I, Mizushima T, Komatsu M, Simonsen A. (2014): Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures.EMBO Rep. May 1;15(5):557-65