Dr. Alanna Watt is an Associate Professor in the department of biology at McGill University, Canada, and has been running the Watt Lab since 2011. The Watt Lab focuses on studying the brain in Spinocerebellar Ataxia Type-6 (SCA6), and Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) using mice. Dr. Alanna Watt gave a talk on her lab’s research in SCA6 at the International Congress for Ataxia Research (ICAR) in November 2024.
What is Brain-Derived Neurotrophic Factor (BDNF), and why did you and your lab become interested in it in SCA6?
Research has shown that in parts of human brain tissue studied after death, there is a reduction in a protein called Brain-Derived Neurotrophic Factor (BDNF). BDNF helps cells in the brain and spinal cord survive, grow and maintain themselves during development. You can think of it as fertiliser for the brain.
We were interested in levels of BDNF in the cerebellum, the part of the brain that controls movement, co-ordination and balance, as this brain region is most affected in ataxias such as SCA6. In mice with SCA6, we found that there were low levels of BDNF only in the cerebellum, and this occurs around the time of disease onset. Researchers at the Mizusawa group in Japan have also previously showed that levels of BDNF are low in the cerebellum of humans with SCA6.
I understand that your work so far has involved comparing mice with SCA6 to healthy mice after administering either an exercise regime or a drug called 7,8-DHF that activates the same pathway as BDNF in the mouse cerebellum, or a combination of both. Can you explain how and why you did this and the results you found.
Research has shown that exercising can increase levels of BDNF in parts of the brain in healthy people, and is beneficial for cell growth and development. So, we wanted to see if exercise in SCA6 mice would increase BDNF levels in the cerebellum. We found that exercise did increase BDNF levels in the SCA6 mouse cerebellum.
There is a drug called 7,8-DHF which has been shown to act on the BDNF signalling pathway in the brain, which we were able to confirm in healthy mice. We wondered if giving this drug to mice with SCA6 might increase BDNF levels in a way similar to exercise – ‘exercise in a pill’. We saw that 7,8-DNF did increase BDNF levels by amounts similar to exercise. This is especially relevant in SCA6, as the condition makes it harder for those affected to exercise as much as healthy people.
SCA6 is a later-onset Ataxia, with disease onset typically around middle age. During which period of the SCA6 disease process (e.g. before, at, or after onset) did you see that it was most beneficial to administer 7,8-DHF in SCA6 mice, and what could this mean if we test it in human SCA6 patients?
In our mice with SCA6, we were not able to see any benefit from administering 7,8-DHF later in the progression of the disease. We do not know yet why this is.
It may be that different processes are driving the disease progression at any given time after onset, and so it may not be one pill that treats the disease throughout. Rather, it may be more about tailoring treatment at each different disease stage.
We have seen that giving the drug around the time of disease onset is most effective. It might even be possible to delay the disease onset with this drug. This means that early intervention may be the most appropriate, which can be difficult in a condition that does not show symptoms until later. So, if people know that the mutation for SCA6 is in their family, they may be able to explore how to boost their BDNF levels.
Could 7,8-DHF potentially treat other types of ataxias? Have we seen research in other ataxias already?
In SCA1, levels of BDNF in the cerebellum are also reduced. There has been some research from the Cvetanovic lab in Minnesota, showing that giving mice with SCA1 BDNF directly can boost its levels in the cerebellum. So, it is possible that there may be a group of ataxias in which BDNF levels are altered, and can therefore be treated.
You mentioned in your talk at ICAR 2024 that we might be able to repurpose other already approved drugs for other conditions, that affect BDNF pathways, for treating SCA6. Why might drug repurposing be beneficial rather than trying to gain approval for a new drug for SCA6?
There are other drugs that work by altering BDNF levels in the brain, since BDNF levels are changed in a number of conditions including Alzheimer’s disease. In SCA6, we might be able to study drugs that act on BDNF pathways that have already been approved by drug regulators. This means that some stages of the clinical trials process can be made shorter, as there is already research on the effects of these drugs. As ataxias are rare diseases, there are not many people who can participate in studies, making it harder to research the effects of drugs. So, being able to repurpose drugs already approved to treat other conditions helps to overcome this problem.
What are your plans for this research going forward?
We are reaching out to clinicians to see if we might be able to study BDNF in patients with SCA6. I also have a graduate student in the lab looking at other drugs that have been shown to affect BDNF in other brain regions.
One of my students in the lab is researching why some parts of the brain are more able to resist cell death than others. We see patterns in resistance to cell death in SCA6, as well as in other ataxias. Knowing why some types of cells are more able to survive in the brain than other means we can try and apply the mechanisms the brain naturally uses to protect itself to treating disease. We call these ‘mechanisms of resilience’.
To read more about the research being carried out at the Watt Lab, click here.
