Written by Anna Cook Edited by Dr. David Bushart

Brain-derived neurotrophic factor can prevent ataxia in SCA1 mice. New research shows that the treatment works even if it’s started after mice develop signs of ataxia.

SCA1 is a neurodegenerative disease caused by a mutation in the Ataxin1 gene. People with SCA1 often develop symptoms around 30-40 years old, although this can vary. The most common symptoms include ataxia, or movement problems that make it difficult to move and walk. These symptoms get progressively worse, eventually leading to problems with swallowing or speaking. There is currently no cure for SCA1 so it is important that research is conducted into potential treatments.

The lab of Dr. Marija Cvetanovic at the University of Minnesota has been using a mouse model of SCA1 to try to identify new treatments. In the past, these researchers have shown that a molecule called brain-derived neurotrophic factor (BDNF) could delay the onset of ataxia in a mouse model of SCA1.

BDNF is a molecule found in the brain that is very important for healthy brain development. It is needed to keep many processes in the brain working normally. The researchers showed that levels of BDNF were reduced in the brains of SCA1 mice. The researchers injected BDNF into the brains of these mice to try to make up for the lost BDNF. This treatment, before the mice had begun to develop symptoms of ataxia, prevented the onset of motor problems and Purkinje cell death. You can read more about those findings in this past SCASource article.

This previous work was very promising, but there was one problem. In this study, the treatment was only tested before the SCA1 mice developed signs of motor problems or changes in their brains. In the real world, if we want to help SCA1 patients, we need treatments that will work even once the disease has started to progress. It was therefore important for the researchers to find out whether this treatment would work later in disease progression. That is exactly what they did next: In December 2020, the Cvetanovic lab published the results from their study testing BDNF as a treatment after mice had started to develop signs of SCA1.

In this study, the researchers used a mouse model for SCA1. These mice have a mutation in their Ataxin1 gene, just like SCA1 patients. These mice develop motor problems similar to those seen in patients. Researchers can also see pathological changes in the brains of the SCA1 mice. Just as they had done before, the researchers carried out surgery on the mice to give them a special pump to deliver BDNF to their brains. This time, they started delivering the BDNF treatment when the mice were 14 weeks old. This is after the mice have developed ataxia, and after pathological changes in the cerebellum have already started to occur. The researchers found that the pump was able to boost levels of BDNF in the SCA1 mouse brain to similar levels that are seen in healthy mice.

To test whether the BDNF treatment worked, the researchers used the rotarod assay to test their motor function and detect any signs of ataxia. The rotarod test is commonly used by ataxia researchers, and involves placing the mice on a rotating rod. The mice have to stay on top of the rod as it moves. Mice that have motor problems like ataxia will fall off faster than healthy mice.

The researchers tested the mice on the rotarod before, during and after the BDNF treatment. Before the treatment, all of the SCA1 mice stayed on the rotarod for a much shorter time than the healthy mice. After 2 weeks of BDNF treatment, the performance of the treated SCA1 mice had improved compared to the SCA1 mice that didn’t get the treatment. However, the SCA1 mice treated with BDNF still did not perform as well at the test as the healthy mice.

The researchers continued BDNF treatment for 4 weeks. Then they tested the mice on rotarod again 1 week after the treatment ended. Once the treatment had ended, the BDNF-treated SCA1 mice only performed slightly better than the ones that didn’t get BDNF. Therefore, the positive effect of BDNF might be time limited and the effects might not last after the treatment is stopped. Further research will be needed to find out whether continuous treatment might be able to produce long-term benefits.

Looking inside the brains of the treated mice, the researchers saw that the BDNF treatment also improved some signs of damage that SCA1 causes in the cerebellum. The cerebellum is the part of the brain that is particularly affected in SCA1 patients and SCA1 mice. In particular, the Purkinje cells in the cerebellum tend to degenerate and are lost in SCA1. Interestingly, the BDNF treatment stopped some of this degeneration. The researchers had also shown in the past that SCA1 mice have an increase in something called astrogliosis. This a process that involves changes to cells in the brain called astroglia. Astrogliosis is usually a sign of disease or injury in the brain. Interestingly, astrogliosis was reduced by BDNF treatment in the SCA1 mice.

These changes are a positive sign that the BDNF treatment may be able to stop some of the changes in the brain that lead to SCA1 symptoms. However, it is important to note that there were still some differences in the brains of the BDNF treated SCA1 mice compared to healthy mice. Some of these changes had been prevented by the pre-onset BDNF treatment from the researchers’ earlier study, suggesting that early intervention may produce the best results.

These results are promising as they show that BDNF could reverse some signs of SCA1 even when the treatment is started after onset. BDNF has also been shown to be a promising therapy in other mouse models of diseases like Alzheimer’s disease. It is important to note that there will need to be more research before this treatment can be tested in humans. The way the BDNF was delivered in this study involved brain surgery and a pump to deliver BDNF, which is not something that can currently be done in patients. We also don’t understand the other effects that BDNF might have on the brain, as BDNF is involved in many processes like learning and memory. Delivering new substances to the brain could have all sorts of unpleasant side effects.

However, there is hope that this research could be used to develop new treatments for SCA1. Scientists may find new ways of safely giving BDNF to patients, or use other drugs that act in a similar way. With more animal studies, researchers may discover new treatments that could be tested for use in SCA1 patients.

Key Terms

Ataxin-1: Ataxin-1 is a small molecular machine known as a protein. Its function is to guide the creation of other proteins from our DNA blueprint, making it an incredibly important indirect player in a variety of cellular processes. When the gene encoding ataxin-1 undergoes a rare mutation that elongates the resulting protein, the result is SCA1.

Brain-derived neurotrophic factor (BDNF): BDNF is a protein found in the brain and the blood that is needed for the brain to develop normally. It is also involved in many processes such as learning and memory and seems to be important to keep the brain working in a healthy way. BDNF levels in the brain are reduced in many different disorders that affect the brain. 

Mouse Model: Researchers can use mice that mimic the effects of diseases. For example, a mutation that leads to ataxia in patients can also cause ataxia in mice. This allows for the study of various aspects of a human disease/condition.

Purkinje Cells: A type of neuron in the cerebellum. They are some of the largest cells in the brain. They help regulate motor coordination.  Purkinje cell loss or changes to Purkinje cell function are common features in cerebellar ataxia.

Rotarod: The rotarod is a technique that has been used for decades to test motor performance in mice and rats. Researchers place the animal on a rotating cylinder and record how long it takes for the animals to fall off as the rotation speed is gradually increased. The higher the mouse/rat’s motor performance, the longer they will be able to stay on.

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Article Reviewed

Sheeler C, Rosa JG, Borgenheimer E, Mellesmoen A, Rainwater O, Cvetanovic M. Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis. Cerebellum. 2021 Jan 4. doi: 10.1007/s12311-020-01226-3. Epub ahead of print. PMID: 33394333.