John Christianson: Cleaning up misfolded proteins

Q: Why is it important for the body to clean up proteins?

John Christianson: Proteins are the machinery of the body, and like any machine, it is important that it functions correctly. This usually happens in the cells, and the cells are pretty good at making the proper architecture and structure. But occasionally, under certain conditions and if you have any changes in the genome, those proteins are not made correctly. When they are not made correctly, the cell has a problem and has to get rid of them.

Q: What part of this process does your research focus on?

JC: My lab works on the degradation mechanisms: how those misfolded proteins are recognised as misfolded and differentiated from those that are correctly folded, and then how that misfolded protein is targeted for degradation and proteolysis within the cell.

Q: What kind of things can happen when this process goes wrong?

JC: Misfolded proteins are bad for the cells. Misfolding can cause one of two things: if the misfolded protein is made incorrectly and destroyed, then we end up with a loss of function. An important gene that the cell needs to survive is then lost, and the cell dies or malfunctions.

A common example is the gene responsible for the disease cystic fibrosis. This is a protein that has a single point mutation that causes that protein to not be made at the level it should be made. When this protein is not made, we end up with a physiological manifestation that is the cause of the disease.

The other issue that may happen when a protein misfolds is that it is not recognised for degradation when it should be and these are commonly called protein aggregation diseases. These are at the heart of neurodegenerative diseases such as Alzheimer's and Huntington's disease.

Q: What are the most important lines of research that have emerged in the last 5-10 years?

JC: One of the things that we are starting to appreciate is the diversity of regulations that goes on in overseeing protein misfolding - what we like to call quality control. There are large gene families within the cell that generate proteins that are responsible for overseeing the integrity or the fidelity of the proteome. A real advance over the last 5-10 years is an appreciation for the diversity of how this system works.

The other very interesting aspect is the idea that you can use degradation as a potential target for therapeutics. One of the best examples is the drug Bortezomib or Velcade® which has been used to target multiple myeloma and certain other haematological malignancies. These small molecules work by inhibiting the degradation process, which leads to an increase in the level of cellular stress to the point where the cells are no longer able to function. In a normal cell that would be bad but in a cancer cell this is what we want to do: we want to kill that cancer cell, and this is a specific way to target those particular cancer cells.

Q: Why does this line of research matter and why should we put money in to it?

JC: From my perspective, we work on basic molecular mechanisms trying to understand the root cause of cellular functions which underlie many different kinds of disease. We are working to try to delineate the components that are responsible for maintaining, in our case, quality control or fidelity of the proteome. We look at these processes in normal cells and also when this process malfunctions, as a way to identify components that may be suitable for therapeutic interventions.

Q: How does your research fit in to translational medicine within the department?
JC: The department has a broad range of interests and my lab works particularly at the basic level. We are interested in trying to understand molecular components and identifying those that are important in this process. The long term goal with collaborators and colleagues within the department is to develop targets and assays that may be suitable for development of therapeutic interventions in the form of small molecules.