Identifying serotonin receptors as a therapeutic target for SCA3

Written by Dr. Hannah K Shorrock Edited by Dr. Hayley McLoughlin

A C. elegans model of SCA3 helps to identify the serotonin receptor agonist befiradol as a potential therapeutic for SCA3

To move toward treatments for ataxia patients, it is important to understand what cellular and molecular pathways are dysfunctional in the disease. We can then identify specific cellular or molecular targets that are suitable for therapeutic intervention. In this study, researchers built on their previous work that adjusting serotonergic signaling could be used as a treatment approach in SCA3. They did this by identifying two drugs that target different combinations of serotonin receptors. When used together, these two drugs provide therapeutic benefit in Caenorhabditis elegans (C. elegans) models of SCA3. This study moves us closer to therapies for SCA3 by identifying the parts of the serotonergic signaling pathway most suitable to be targeted for further drug development.

The research team had previously worked with a small molecule that targeted multiple cellular pathways. This included many components of the serotonergic signaling pathway. In this study, the group wanted to identify the aspects of this signaling pathway responsible for the therapeutic benefit seen with these treatments. They used a C. elegans animal model of SCA3 in which a form of the SCA3 causing gene, ATXN3, containing 130 CAG repeats is expressed in neurons.

C. elegans have four receptors within the serotonergic signaling pathway that are highly similar to four receptors in humans. This makes them a strong model system to explore the treatment potential of targeting these receptors. The mutant ATXN3 C. elegans move less and they move slower than C. elegans without the ATXN3 expansion.

The group studied the effect of two drugs targeting receptors involved in the serotonergic signaling pathway on these movement defects. They found that at the same concentration both tandospirone and befiradol treatment for four days improved the motor performance of mutant ATXN3 C. elegans. This occurred for both the speed and amount of movement. Importantly, neither of the drugs affected the motor performance of C. elegans without the mutant ATXN3. This indicates that in this model system, the effect of the treatments is specific to the presence of the repeat expansion mutation. This is a desirable quality for any therapeutic strategy for a repeat expansion disease.

Two large blue worms on a black background, with three smaller blue worms beneath them
Microscopy images of C. elegans worms, a type of animal model used to study ataxia. Photo used under license by Heiti Paves/
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SCAsource is Partnering with the National Ataxia Foundation

The SCAsource team is excited to announce that we are partnering with the National Ataxia Foundation (NAF) to improve our website infrastructure!

As you know, SCAsource is run by a team of volunteers, mainly graduate students and post-doctoral fellows from ataxia research labs. We’re researchers, not web designers, but we’ve done our best so far to make the SCAsource website the best it can be.

However, by partnering with NAF we will be able to get support with the administrative aspects of running the SCAsource website. They’ll also be covering our website costs, which will help us grow into a sustainable initiative.

The National Ataxia Foundation Logo.
SCAsource is partnering with the National Ataxia Foundation to improve our website infrastructure and cover our administrative costs. Image courtesy of the National Ataxia Foundation

Over the next few months, we’ll be migrating existing SCAsource content to a new section of the NAF website. We’re planning to have this finished by July 2022. But don’t worry! This current website will still be online for a while. You will be automatically redirected to the new website if you click the link of an old SCAsource article.

We are so excited for this next step in the growth of SCAsource! We’ll keep you updated as our transition to the new website progresses. Thank you to all our volunteer writers, editors, and translators who have made the idea of SCAsource a reality. Another huge thank you to you, our readers! Thanks to your interest and support, we’ve been able to partner with NAF.

You can learn more about the National Ataxia Foundation at its website. You can read more about our partnership in the official press release or the announcement video on Youtube.

Cerebellum, Pons, and Medulla- Oh my! Which brain regions can help us assess SCA3 progression?

Written by Carrie Sheeler Edited by Dr. Hayley McLoughlin

Researchers use Magnetic Resonance Imaging (MRI) to determine if brain volume can be a biomarker for SCA3

There are two goals of preclinical research. First, to understand the cause of a disease. Second, to develop treatments to stop or slow its effects. As understanding of the underlying causes of spinocerebellar ataxias (SCAs) has grown, researchers have begun to develop strategies for treating or slowing the progression of this family of diseases. The next question is how to best move these potential therapies from the lab space to the clinic, which we do through clinical trials.

Clinical trials are essentially enormous multi-phase experiments run largely by drug companies. Clinical trials ask two main questions. First, is this drug/therapy safe? Then, how well does this drug/therapy work? Many potential therapies for neurodegenerative diseases have been unsuccessful in the past decade. These attempts have failed to demonstrate that they are effective in changing the progression of diseases, such as Alzheimer’s and Parkinson’s. There is concern that lack of drug effectiveness may come from starting treatment too late in the progression of the disease. Later in disease, irreversible damage may have already happened that is too much to fix. This is difficult to avoid in cases where the main measure of drug success (known as “primary endpoint”) is determined by clinical assessment in which a patient treated with a drug already has symptoms. An example of this in ataxia clinical trials is using the scale for assessment and rating of ataxia, also known as the SARA score.

To add more quantitative strength to clinical assessments that may also allow researchers to predict when symptoms will start to occur, scientists are seeking out new ataxia biomarkers. Examples of biomarkers include changes in brain volume or the concentration of certain proteins in blood. These studies may allow for a greater timeframe within which clinicians can combat disease progression

Abstract blue brain
The volume of different brain regions could be used as biomarkers for SCA3 clinical trials. Photo used under license by Butusova Elena/

This paper examined if the volume of specific areas of the brain may be used as a biomarker for spinocerebellar ataxia type 3 (SCA3). To accomplish this aim, they assessed brain images from 210 symptomatic SCA3 individuals, 48 pre-ataxia SCA3 individuals, and 63 healthy controls. The designation of ataxia vs pre-ataxia was done using SARA score. Pre-ataxia individuals had a score of less than three, while symptomatic patients had a score greater than or equal to 3. The images were taken using magnetic resonance imaging (MRI). Images were taken of 122 distinct brain regions, covering the entirety of the brain and the upper regions of the spinal cord.

The average ages for all three groups were 46 for symptomatic individuals with SCA3, 38 for pre-ataxia individuals with SCA3, and 43 for controls. Notably, each patient received only one MRI. This means the comparisons made in this study rely on comparisons between individuals, rather than within the same individual over time. This is important because it means that the results listed below are a representation of changes in the brain across a population of SCA3 mutation carriers. This is not a representation of what is happening in one individual over time. But it is quite similar to what you might measure during a clinical trial.

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Measuring neurodegeneration in spinocerebellar ataxias

Written by Dr Hannah K Shorrock Edited by Dr. Maria do Carmo Costa

Neurofilament light chain predicts cerebellar atrophy across multiple types of spinocerebellar ataxia

A team led by Alexandra Durr at the Paris Brain Institute identified that the levels of neurofilament light chain (NfL) protein are higher in SCA1, 2, 3, and 7 patients than in the general population. The researchers also discovered that the level of NfL can predict the clinical progression of ataxia and changes in cerebellar volume. Because of this, identifying patients’ NfL levels may help to provide clearer information on disease progression in an individualized manner. This in turn means that NfL levels may be useful in refining inclusion criteria for clinical trials.

The group enrolled a total of 62 SCA patients with 17 SCA1 patients, 13 SCA2 patients, 19 SCA3 patients, and 13 SCA7 patients alongside 19 age-matched healthy individuals (“controls”) as part of the BIOSCA study. Using an ultrasensitive single-molecule array, the group measured NfL levels from blood plasma that was collected after the participants fasted.

The researchers found that NfL levels were significantly higher in SCA expansion carriers than in control participants at the start of the study (baseline). In control individuals, the group identified a correlation between age and NfL level that was not present among SCA patients. This indicates that disease stage rather than age plays a larger role in NfL levels in SCAs.

Looking at each disease individually, the group was able to generate an optimal disease cut-off score to differentiate between control and SCA patients. By comparing the different SCAs, the research group found that SCA3 had the highest NfL levels among the SCAs studied. As such, SCA3 had the most accurate disease cut-off level with 100% sensitivity and 95% specificity of defining SCA3 patients based on NfL levels.

Artist's drawing of a group of Laboratory Scientist sturying a larger-than life human brain
A team from the Paris Brain Institute identify that SCA1, 2, 3, and 7 patients have higher levels of NfL protein than the general population. Photo used under license by ivector/
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Snapshot: What is the Pole Test?

The pole test is a common and straightforward test to assess motor coordination in mice. While ataxia might be easy to see in patients, it is not always as apparent in ataxia mouse models. Therefore, this fast and simple test is important for researchers to measure disease severity. It is also important to test the effect of different treatment strategies.

Small experimental mouse is on the laboratory researcher's hand with blue gloves
 Photo used under license by unoL/

How is the pole test performed?

At the beginning of the test, the mouse is placed facing upward on the top of a long pole. The researchers then measure the time the mouse takes to turn around and climb down to the bottom of the pole. A healthy mouse typically takes 10-20 seconds to perform the task. If the mouse struggles and takes a long time to get to the bottom, it suggests that the mouse has motor coordination deficits.

Researchers commonly use the pole test because it’s a quick way to assess coordination in mice, even before the mice show obvious ataxia symptoms. The pole test takes about 5 minutes per mouse. It is thereby much faster than other motor coordination tests, such as the rotarod test, typically performed over multiple days. Another advantage is that the pole test can be repeated on the same mice multiple times. This allows for tracking how a mouse’s motor coordination changes over time.

0 seconds - mouse is at top of a pole facing upward. 5 seconds - mouse climbs to the top of the pole to turn around, so it can face down towards the ground. 10 seconds - mouse has climbed down the pole
Cartoon of mouse performing the pole test. Time is shown in seconds. Image courtesy of Eder Xhako.

How is the pole test used in literature?

One example of the pole test being used in the literature is a study by Nitschke and colleagues. In this study, the researchers identified a small regulatory RNA, miR760, that regulates the levels of ATXN1. ATXN1 is the gene that causes Spinocerebellar Ataxia Type 1 (SCA1). The group showed that injections of miR760 in the brain decreases ATXN1 protein levels in a SCA1 mouse model. The researchers then used the pole test to measure how the treatment with miR760 would affect the ataxia phenotype in the SCA1 model. They found that one month after the treatment the mice displayed improved motor coordination compared to control mice.  

If you would like to learn more about the Pole Test, take a look at this resource by Melior Discovery. You can learn more about other motor coordination tests in our past Snapshots on the Rotarod Test.

Snapshot written by Eder Xhako and edited by Dr. Larissa Nitschke.