The combined efforts of researchers from New Zealand, UK, Switzerland, Italy and USA have identified a potential therapeutic candidate for Huntington’s disease: an enzyme called TANK binding kinase 1 (or TBK1 for short).
When the gene for the huntingtin protein (HTT) has a certain genetic mutation, it causes the clumping together of the HTT protein. For a cell to function properly, it must have control of all the things inside of that cell, and the clumping together of HTT protein is something the cell cannot control. This clumping is toxic to the cell and eventually leads to Huntington’s disease (HD). One way HD researchers are looking to treat HD is by giving cells the tools they need to regain control and prevent protein clumping.
In previous research, a small modification of the HTT protein (adding a couple of phosphate groups) was shown to reduce its ability to clump together. These results were promising, but they were from experiments in an artificial setting (cells in a petri dish), so the researchers from this latest study sought to back up these findings by looking at the modification of HTT protein in a more relevant system. They were able to identify an enzyme – TBK1 – that could add phosphate groups to HTT protein in the exact same way that was seen previously. Increasing the amount of this enzyme produced several benefits, the main one being the prevention of HTT clumping. These findings were very exciting, and the obvious next step was to validate the results in humans.
Cartoon depiction of TBK1 enzymes (orange) adding phosphate groups (yellow) to the HTT protein (green).
To investigate the relationship between TBK1 enzyme and HTT protein in the human brain, the researchers needed the resources and expertise of our scientists here in New Zealand. This is because researchers at The University of Auckland have unique access to two key resources that are sought after: The Neurological Foundation Human Brain Bank and the tissue microarray. The Neurological Foundation Human Brain Bank is an invaluable collection of post-mortem human tissue collected over many years. Our scientists also have the expertise of the tissue microarray, which is a remarkable technique that allows the efficient screening of multiple samples on a single microscope slide.
Example of a tissue microarray. 28 disease samples and 28 control samples were stained simultaneously for the presence of a protein of interest (purple stain). Stars indicate empty slots left for orientation purposes.
These two resources were combined at the University of Auckland to compare the presence of the TBK1 enzyme between a large number of samples with and without HD. While no significant difference in the amount of TBK1 enzyme was found between these sample sets, researchers were able to show the TBK1 enzyme is both present and active in the human brain. This is an important result as, before this research, the modification of HTT protein was simply an interesting idea. Now, we have an enzyme that is known to be active in the human brain and could play a role in reducing the toxic effects of HTT clumping. If scientists are able to figure out a treatment that can safely target the TBK1 enzyme (or perhaps one like it) and increase its activity in humans, this represents a potential therapy for HD.
Huntington’s disease is unique in that its cause is known and can be tested for at any age, making HD an excellent candidate for preventative treatment. This is because a diagnosis can made years before symptoms become apparent and therefore treatment may begin before damage occurs. As long as researchers within New Zealand and around the world are looking for one, there is hope.
Want to know more? Check out the article published in The EMBO Journal here: https://www.embopress.org/doi/full/10.15252/embj.2020104671
Remai is a developmental research technician in the Neurological Human Brain Bank at the University of Auckland. She has a background in both genetics and biochemistry and has a strong interest in studying heritable human disease at the molecular level.
