“Autophagy is involved, in Type 2 diabetes, in neurodegenerative processes, in cancer… incidentally, many diseases that affect us as we age.”
Dr. James T Murray, from the School of Biochemistry and Immunology at the Trinity College in Dublin, gave a seminar at our Institute last month. It was a very interesting talk, mainly about how autophagy is involved in Parkinson’s disease. Just before the talk we had the chance to ask him a few questions…
- What is autophagy?
Cells get damaged. It is like a car: you have to service it; you have to put fuel into it, clean it, otherwise it doesn’t work as well. The autophagy pathway is a little bit like the servicing system for the cell. There are damaged materials, damaged organelles, misfolded proteins, and physiological stressors that cells must deal with. Autophagy is the mechanism by which the damage is removed before it becomes detrimental to cell viability. All eukaryotic cells have it so that they can be protected against environmental stress.
- How does it work?
It is similar to the endocytic pathway: a cellular structure is formed around the damaged material, to enclose it, that will eventually merge with a lysosome for the contents to be degraded. What is different, though, so the cell doesn’t get confused, is that in the autophagy pathway the vesicle has a double membrane, whereas in the endocytic pathway it is single. This double membrane vesicle that forms is called the autophagosome, and is usually spherical in shape. After the autophagosome finds and fuses with a lysosome, lysosomal enzymes begin to chop everything up, obtaining free fatty acids, amino acids, etc., and all the damaging materials are recycled.
- Why is it that we get old if our cells are recycling themselves to become new all the time?
My thinking is because the autophagy pathway becomes less profficient when we get older. This is because either the signals that control the autophagy pathway become less able to stimulate the response, the ability to package up damaged material is less efficient, or the amount of damage that needs clearing becomes too great for utophagy to cope with.
What I find fascinating is there is a little and very interesting organism, a salamander type creature that is called the olm, which lives in caves and can live for more than a hundred years. There is no natural light; there are no natural toxins, nor any predators in their environment. Once removed from normal physiological stresses they have adapted to a very long life span, for several reasons. I wonder whether there is anything special about their autophagy. If I had the opportunity, I would study the Olm.
- Aubrey de Grey is a British gerontologist who claims that, when we are able to fix the damage that we accumulate in our cells during our lives, humans will live for more than 1000 years…
No. I doubt we will ever live to 1000. We will get killed before that, we will probably be hit by a car! (Laughs) Theoretically I suppose yes, because if you can limit the amount of damage that occurs in tissues and organs, then there is no reason why cells, tissues and thus organisms can’t last for much longer periods of time, but to get to that point we would need a much greater understanding of ageing at a systemic level to be able to make the kinds of advances required to live so long.
- How can a cell know that it must recycle a specific organelle?
Well, I will use the example of the mitochondria. When this organelle works properly, a protein called PINK1 is constantly moved from the outside of the mitochondria, to the inside, where it is processed, then degraded. However, when mitochondrial function is compromised, PINK1 accumulates on the surface of the mitochondria, and this generates a signal that makes another protein, Parkin, functional. Parkin then activates other surface molecules, and these molecules act as signalling clues for destruction leading to selective autophagy of mitochondria, which is called mitophagy.
- What happens if the autophagy mechanism is not working properly?
Any fluctuations in normal autophagy have detrimental effects: both underactivity or the over-activity, and can lead to disease. Autophagy is involved, in Type 2 diabetes, in neurodegenerative processes, in cancer… incidentally, many diseases that affect us as we age.
- What happens in cancer?
It is complex: depending on the stage of the disease, autophagy is increased or decreased. In early stages of neoplastic diseases, autophagy is attenuated: there is an accumulation of damage that will produce the genetic lesions to activate oncogenes. This makes sense, because autophagy normally functions to eliminate damage, and so has what we consider tumour suppressor function. Then, when the primary tumour mass is forming, tumour cells and the surrounding normal tissue increase autophagy activity to provide nutrients for tumour cell growth and proliferation. Then, later, whenever tumours break away and tumour cells arrive at distant micrometastatic lesions through the circulation, autophagy comes into play again… It comes in waves that are complicit in cancer progression.
- And is any of the therapies used nowadays to treat cancer using the autophagy mechanism as their target?
One of the key responses to current chemotherapeutic drugs is chemotherapy resistance: patients become resistant to their first line treatment. In these chemoresistant tissues, the autophagy pathway frequently becomes activated, which is not surprising: you are insulting a tumour with a very large quantity of a toxic compound, so it will mobilize the autophagy pathway to try to limit damage. A new therapeutic strategy that is being explored is to deliver a combination treatment with standard chemotherapy agents and a drug that block the autophagy pathway, which currently are drugs that block lysosome activity. Drugs that are more selective for autophagy inhibition are still in the early stages of research development. We are also not certain of the long-term secondary effects of using specific autophagy inhibitors as drugs. So, yes: autophagy can be a very good druggable target, but it is unlikely that this strategy will work well enough on its own; modern oncology is tending towards multidrug cocktails.
- Today you are going to talk about autophagy in Parkinson’s disease. What is the relation between them?
Autophagy is essential for most aspects of the physiology of Parkinson’s disease. It is a multifactorial disease, which can be produced for many different kinds of protein mutations: in α–synuclein, in LRRK2, in PINK1, etc. These mutations can produce mitochondrial damage, which can eventually lead to an energy stress that can overwhelm and poison the autophagy pathway.
- What are you team currently working on?
Oh GOD, we work on a lot of different things!
Basically, we are interested in protein kinases and cell signalling processes that regulate autophagy. We study how these processes are involved in Parkinson’s disease, cancer, Alzheimer’s disease, type 2-diabetes, and also a rare disease called cystinosis. Well, and we also have a project on microglial function…the key point though is that much of the signals are common and so we can use our expertise to understand autophagy signaling in different contexts.
- If there was fire, and you could just safe one of your papers, which one would it be?
This is a hard one…! I think my first paper, as a PhD student. It was not a very spectacular publication, but it was my first. It was about kinases in macrophages, and I was very very proud of that work because I was able to mix enzymology, protein biochemistry and cell biology. That paper has really been the template approach I have tried to apply throughout my research career.
Roser Bastida Barau