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National Ataxia Foundation


Brain-derived neurotrophic factor: A new (old) hope for the treatment of SCA1

Written by Eviatar Fields Edited by Dr. Vitaliy Bondar

Scientists use Brain Derived Neurotrophic Factor to delay motor symptom onset and cell death in a mouse model of Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is a rare neurodegenerative disease that affects about 2 out of 100,000 individuals. Patients with SCA1 present with motor symptoms such as disordered walking, poor motor coordination and balance problems by their mid-thirties and will progressively get worse symptoms over the next two decades. No treatments for SCA1 exists. These motor symptoms cause a significant decrease in patient independence and quality of life. Scientists use mouse models that recreate many SCA1 symptoms to understand the cause of this disease and test new treatments.

In this paper, Mellesmoen and colleagues use a mouse model of SCA1 which presents with severe motor symptoms by adulthood. In order to measure the severity of the motor problems in the SCA1 mouse model, the researchers use a test called a rotarod. The rotarod test is similar to a rolling log balance: mice are placed on a rotating drum that slowly accelerates. Mice that can stay on the drum for longer durations have better motor coordination than mice who fall off the drum earlier. Mellesmoen was trying to find a way to get the mice to stay on the drum for longer.

artistic cartoon of male doctor sin from of a microscope and large DNA model
Cartoon of a medical researcher holding a clipboard.

Purkinje cells, the main cells of the cerebellum, eventually die in SCA1 mouse models and in patients later in life. However, it remains unclear how and why these brain cells, which are responsible for the fine-tuning of movement and motor coordination, die. This is an important question as its answer might lead to new treatments that prevent brain cells from dying which might improve SCA1 symptoms. One possibility is that some changes in gene expression (that is, how “active” or “inactive” a gene is) causes the cells to die in SCA1 mice. To test this hypothesis, the authors used a technique called RNA-seq to examine how gene expression is altered in SCA1 mice compared to healthy mice.

Genes are the blueprints for the proteins that allow our bodies to properly function. In order to build a protein, these blueprints must be copied from a gene into a messenger called mRNA that will translate that information into a protein. The amount of and proper functioning of proteins usually depends on how much of its mRNA is present in a cell, which depends on whether its gene is turned on or off. In many diseases, some genes are expressed more and some less than in healthy individuals. This leads to differences in mRNA and can change a protein’s function. RNA-seq is a tool that allows us to see changes in the expression of genes so that we can better understand why proteins aren’t working properly and target therapies aimed at restoring their normal function. In other words, genes are like books in a library and RNA-seq is a way to determine which books are being checked out, what information is being taken from them, and how much of that information is being used.

Mellesmoen and colleagues used RNA-seq to examine changes in gene expression in a mouse model of SCA1. They found that in young SCA1 mice, the expression level of the gene coding for the Brain-Derived Neurotrophic Factor (BDNF) was higher than in healthy mice of the same age. However, when they looked at older mice, BDNF gene expression was lower in SCA1 mice compared to healthy mice. Why is this important? BDNF is a protein that has long been known to be neuroprotective, and is critical for a cell’s development, survival and overall health. If there is more BDNF in a young mouse with mild or no symptoms, but less BDNF in an older, symptomatic mouse, BDNF might be a protective factor responsible for delaying the onset of the motor symptoms in younger SCA1 mice.

How might one test this hypothesis? Mellesmoen and colleagues decided to manipulate the levels of BDNF. They used a special pump that continually infused BDNF protein directly into the brains of young mice in a manner similar to the way an insulin pump works for patients with Type-I Diabetes. To make sure that any changes they detected were from BDNF alone and not from the treatment itself, the researchers also tested the effects of a placebo treatment: the artificial cerebrospinal fluid (ACSF) that they used to dissolve the BDNF, which they expected would not have any effect as it mimics the natural fluid in the brain.

After four weeks of BDNF treatment, mouse motor coordination was tested by the rotarod test. Impressively, SCA1 mice that received BDNF treatment were almost indistinguishable from healthy mice of the same age and performed much better than SCA1 mice that received the placebo ACSF. When the researchers examined the amount of cell death in the BDNF-treated SCA1 mice, they found that the treated group had almost no Purkinje cell death, while the control group that received the placebo ACSF had major cell loss. These results suggest that BDNF treatment prevented or at least reduced the death of brain cells in the SCA1 mouse model. BDNF treatment seems to be neuroprotective and delays the onset of the motor symptoms in SCA1 mice. The results from this study add to a growing body of literature showing that BDNF is altered in many neurological disorders such as Down Syndrome, Alzheimer’s Disease and ataxia, giving hope that targeting BDNF could be a promising therapeutic avenue.

Although the results of this study are promising, it is important to note that much more work needs to be done before BDNF can be used as a treatment for SCA1 patients. BDNF acts in a number of extremely complex manners in the brain, and although the results of this study tell us that giving SCA1 mice BDNF protein will improve their symptoms, it does not tell us how. Without the knowledge of how BDNF acts in the brain, it would not be safe to provide humans with high quantities of this protein. It is important to have multiple, thorough studies in mice as well as clinical trials in humans to test the efficacy and safety of any drug treatments. Nevertheless, the important results made by Mellesmoen and colleagues provide a promising therapeutic target for the treatment of SCA1 to improve not only the quality of life in those suffering from SCA1, but possibly even preventing or delaying the fatal outcome of the disorder.

Key Terms

Age of Onset: The age develops or acquires a specific condition or symptoms of a disorder.

Protein: A molecule determined by a specific sequence of dna. These molecules have a specific function in cells, tissues, and organs.

RNA: Ribonucleic acid. This molecule copies the information encoded in genes (which are made of DNA) and functions as a blueprint for making proteins in a cell. Learn more about RNA in this SCAsource Snapshot.

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 animal motor performance, the longer they will be able to stay on.

Transcription: The process in which the genetic information from DNA is copied into RNA, another medium for genetic information.

Conflict of Interest Statement

Eviatar Fields is a Ph.D. student at McGill University, and claims no conflicts of interest with the studies referenced in this article. The editor declares no conflict of interest.

M. Cventatonic and C. Sheeler, who are part of the team that conducted this research, are contributors to SCAsource. They did not contribute to the writing or editing of this summary.

Citation of Article Reviewed

Mellesmoen, A., Sheeler, C., Ferro, A., Rainwater, O., & Cventatonic, M.  Brain derived neurotrophic factor (BDNF) delays onset of pathogenesis in transgenic mouse model of spinocerebellar ataxia type 1 (SCA1). Frontiers in Cellular Neuroscience. 2019. 12: 509. (

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