“Expanding” the therapeutic promise for SCA1

Written by Dr. Judit M Perez Ortiz Edited by Dr. Maria do Carmo Costa

A druggable target in Spinocerebellar Ataxia type 1 (SCA1) shows promise in treating cerebellar and non-cerebellar aspects of disease.

Spinocerebellar Ataxia type 1 (SCA1) is a neurodegenerative disease that typically starts with coordination difficulties (ataxia) in mid- to late-adulthood, worsens over time, and shortens life expectancy. SCA1 runs in families, as it is caused by a genetic mutation in a gene called Ataxin-1. The gene’s instructions make a protein conveniently also termed “ataxin-1”. Healthy ataxin-1 is important in orchestrating important processes in brain cells. 

In SCA1, mutant ataxin-1 drives disease by affecting these important cellular processes. In patients with SCA1, their ataxin-1 protein has a polyglutamine repeat expansion mutation that makes the protein behave in toxic ways. The disarray caused by mutant ataxin-1 protein slowly deteriorates and ultimately compromises the health of the brain areas involved. Research on this topic is very rich and increasingly exciting. SCA1 treatments under investigation explore different strategies to minimize the insult caused by mutant ataxin-1.

New work by Nitschke and colleagues takes previous efforts a step further towards this goal by delving deeper into the promises and limitations of an exciting therapeutic “angle” in the ataxin-1 protein itself.

Experimental mice are placed on the rotating rod to animal test in the Laboratory
Research in SCA1 mice shows preventing S776 phosphorylation improved muscle strength, respiratory function, and prolonged lifespan. Photo used under license by unoL/Shutterstock.com.
Continue reading ““Expanding” the therapeutic promise for SCA1”

Snapshot: What is Riluzole?

Riluzole, often sold under the trade name Rilutek, is a medication used for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease that mainly affects neurons controlling muscle movements. The drug was approved by the FDA (1995), Health Canada (1997), and the European Commission (1996). It helps slow down disease progression and may extend patient survival. The medication is available in tablet and liquid form, generally well-tolerated. There are sometimes mild side effects, which may include loss of appetite, nausea, and abdominal pain.

Close up of a woman taking a pill with water
Riluzole has been used to treat ALS, and research has suggested it may also help with forms of ataxia. It is currently being tested in clinical trials. Photo used under license by fizkes/Shutterstock.com.

How does it work?

Exactly how Riluzole slows disease progression remains unknown. However, it is thought that its neuroprotective effects likely stem from reducing a phenomenon known as excitotoxicity.

Neurons communicate with each other through chemical messengers called neurotransmitters. The signalling of these messengers needs to be tightly controlled. Too little or too much signaling will disrupt normal functions of the brain and cause damage to cells. Excitotoxicity is the result of excessive signaling by glutamate, one of the most abundant neurotransmitters in the brain. Glutamate is also associated with many neurodegenerative diseases.

Riluzole prevents this excessive signaling through several mechanisms. It is hypothesized that the effectiveness of riluzole in ALS treatment is the result of this neuroprotective property.

Riluzole for Ataxia

The neuroprotective function of riluzole has been a point of interest for the treatment of other neurodegenerative diseases since its approval. Multiple clinical trials have been conducted for patients with neurodegenerative diseases including Parkinson’s disease, Huntington’s disease, multiple system atrophy, and ataxia.

In 2010, a pilot trial was conducted with 40 patients with cerebellar ataxia who showed a lower level of motor impairment, measured by the International Cooperative Ataxia Rating Scale. A follow-up trial was then performed in 2015 for 55 patients with spinocerebellar ataxia (SCA) or Friedreich’s ataxia. Similarly, patient impairment had improved by an alternative measurement using the Scale for the Assessment and Rating of Ataxia. These findings indicate the possibility of riluzole being an effective treatment for cerebellar ataxia. However, more long-term studies and ones that are specific to different types of SCA need to be conducted to confirm the results.

Riluzole in Development

Even though riluzole was discovered more than 25 years ago, variations of the drug are still under development. As ALS often affects a patient’s ability to swallow, a new formulation of riluzole that is absorbed by placing it under your tongue is being developed under the name Nurtec.

Another prodrug version of riluzole, named Troriluzole (BHV-4157), may be better absorbed by the body with fewer side effects. Troriluzole is currently in phase three clinical trial for patients with different types of SCA. The trial is expected to be complete by November 30, 2021, and will hopefully provide more insight into the effectiveness of Troriluzole in SCA patients.

If you would like to learn more about Riluzole, take a look at these resources by the ClinicalTrials.gov and the Mayo Clinic.

Snapshot written by Christina (Yi) Peng and edited by Terry Suk.

Spotlight: The Cvetanovic Lab

Principal Investigator: Dr. Marija Cvetanovic

Location: University of Minnesota, Minneapolis, USA

Year Founded:  2012

What disease areas do you research?

What models and techniques do you use?

Group picture of 11 people in casual clothing.
This is a group picture of the Cvetanovic Lab from 2021. Back Row from the left to right: Katherine Hamel, Alyssa Soles, Marija Cvetanovic (PI), Austin Dellafosse, Kaelin Sbrocco, and Carrie Sheeler. Front Row from left to right: Laurel Schuck, Ella Borgenheimer, Genevieve Benjamin, Juao-Guilherme Rosa, and Fares Ghannoum. Not Pictured: Stephen Gilliat.

Research Focus

What is your research about?

The human brain is made up of many different types of cells. Each of them has slightly different roles in a healthy brain. The goal of our research is to understand how SCA1 makes these different cells sick in different ways. We want to check if different parts of the brain show distinct or unique changes because of SCA1.

We are also interested in identifying which physical changes in the brain lead to specific SCA1 symptoms. We do a lot of our research on a specific type of brain cell called glial cells.

Why do you do this research?

Most brain research focus on neurons. But 50% of the cells in your brain aren’t neurons, they are glial cells! Glial cells help support and regulate neuronal activity, but they often get overlooked. But more scientists like us are researching glial cells. They do a lot for your brain.

If we want to develop successful therapies for SCA1, we need to understand how glial cells are impacted. Without that knowledge, we will not have the full picture. That’s why we do this work.

Fun Fact

We have a number of fluffy companions in our lab. Please check the Creative Catalysts page of our Lab Website for pictures!

For More Information, check out the Cvetanovic Lab Website!


Written by Dr. Marija Cvetanovic, Edited by Celeste Suart

Interaction of Ataxin-1 and DNA repair proteins contributes to SCA1 disease onset and progression

Written by Dr. By Marija Cvetanovic Edited by Dr. Larissa Nitschke

Suart et al. show that Ataxin-1 interacts with an important DNA repair protein Ataxia telangiectasia mutated (ATM), and that reduction of ATM improves motor phenotype in the fruit fly model of SCA1, indicating DNA repair as an important modifier of SCA1 disease progression.

Each day, due to a combination of wear and tear from the normal processes in the cells, and environmental factors, such as irradiation, DNA in each of our cells can accumulate from 10,000 to 1,000,000 damages. If damaged DNA is left unrepaired, this can lead to loss of cell function, cell death, or a mutation that may facilitate the formation of tumors. To avoid these negative outcomes, cells take care of damaged DNA employing DNA damage response/repair proteins. Ataxia-telangiectasia mutated (ATM) protein is a critical part of DNA repair as it can recognize sites of DNA damage. It also helps recruit other proteins that repair DNA damage.

Mutations in the ATM gene cause autosomal recessive ataxia called Ataxia telangiectasia (AT). AT is characterized by the onset of ataxia in early childhood, prominent blood vessels (telangiectasia), immune deficiency, an increased rate of cancer, and features of early ageing.

An artist's drawing of four strands of DNA
DNA repair may be an important modifier of SCA1 disease progression. Photo used under license by Anusorn Nakdee/Shutterstock.com.

Expansion of CAG repeats in the Ataxin-1 gene causes dominantly inherited Spinocerebellar Ataxia Type 1 (SCA1). A feature of SCA1 is that a greater number of repeats correlates to an earlier age of onset of symptoms and worse disease progression. The connection of DNA repair pathways and SCA1 was brought into focus in 2016 by a study by Bettencourt and colleagues. As longer CAG repeat tracts association with earlier ages at onset do not account for all of the difference in the age of onset authors searched for additional genetic modifying factors in a cohort of approximately 1000 patients with SCAs. They showed that DNA repair pathways significantly associate with the age at onset in SCAs, suggesting that genes with roles in the DNA damage response could provide new therapeutic targets (and hence therapeutics) in SCAs.

In this study, Suart et al. identify ATM as one such gene. Using irradiation and oxidizing agent to damage DNA and using imaging to follow ataxin-1 movement, authors first show that ataxin-1 is recruited to the site of DNA damage in cultured cells. They also demonstrate that SCA1 mutation slows down but does not prevent ataxin-1 recruitment to the sites of DNA damage.

Continue reading “Interaction of Ataxin-1 and DNA repair proteins contributes to SCA1 disease onset and progression”

Spotlight: The CMRR Ataxia Imaging Team

Location: University of Minnesota, MN, USA

Year Research Group Founded:  2008

What models and techniques do you use?

A photo of the CMRR Ataxia Imaging Team
A photo of the CMRR Ataxia Imaging Team in 2019. Front row, left to right – Diane Hutter, Christophe Lenglet (PI), Gulin Oz (PI), Katie Gundry, Jayashree Chandrasekaran Back row, left to right: Brian Hanna, James Joers, Pramod Pisharady, Kathryn France, Pierre-Gilles Henry (PI), Dinesh Deelchand, Young Woo Park, Isaac Adanyeguh (insert)

Research Group Focus

What shared research questions is your group investigating?

We use high field, multi-nuclear magnetic resonance imaging (MRI) and spectroscopy (MRS) to explore how diseases impact the central nervous system. These changes can be structural, functional, biochemical and metabolic alterations. For example, we apply advanced MRI and MRS methods in neurodegenerative diseases and diabetes.

We also lead efforts in research taking place at multiple different cities across the United States and the world. As you can imagine, studies spread out across such a big area require a lot of coordination and standardization. We design robust MRI and MRS methods to be used in clinical settings like these.

Another important question for our team is how early microstructural, chemical and functional changes can be detected in the brain and spinal cord by these advanced MR methods. We are interested in looking at these changes across all stages of disease.

Why does your group do this research?

The methods we use (MRI and MRS) can provide very helpful information to be used in clinical trials. These biomarkers we look at can provide quantitative information about how a disease is progressing or changing.

There is good evidence that subtle changes in the brain can be detected by these advanced MR technologies even before patients start having symptoms. If we better understand the earliest changes that are happening in the brain, this can in turn enable interventions at a very early stage. For example, we could treat people even before brain degeneration starts to take place.

Why did you form a research group connecting multiple labs?

We came together to form the CMRR Ataxia Imaging Team to benefit from our shared and complementary expertise, experience, and personnel. We can do more together than we could apart.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for multiple different studies. You can learn more about the research we are recruiting for at the following links: READISCA,  TRACK-FA, NAF Studies, and FARA Studies. More information is also available through the UMN Ataxia Center.

A photo of the CMRR Ataxia Imaging Team in 2016
A photo of the CMRR Ataxia Imaging Team in 2016, in front of the historic 4T scanner where the first functional MR images were obtained, in CMRR courtyard. Left to right – Christophe Lenglet (PI), Sarah Larson, Gulin Oz (PI), Dinesh Deelchand, Pierre-Gilles Henry (PI), James Joers, Diane Hutter

What Labs Make Up the CMRR Ataxia Imaging Team?

The Oz Lab

Principal Investigator:  Dr. Gulin Oz

Year Founded:  2006

Our focus is on MR spectroscopy, specifically neurochemistry and metabolism studies. We focus on spinocerebellar ataxias. Also, we have been leading MRS technology harmonization across different sites and vendors.

The Henry Lab

Principal Investigator: Dr. Pierre-Gilles Henry

Year Founded:  2006

We develop advanced methods for MR spectroscopy and motion correction. Then apply these new methods to the study of biochemistry and metabolism in the brain and spinal cord in various diseases. We have been working on ataxias since 2014.

Fun Fact about the Henry Lab: The French language can often be heard in discussions in our lab!

The Lenglet Lab

Principal Investigator:  Dr. Christophe Lenglet

Year Founded:  2011

We develop mathematical and computational strategies for human brain and spinal cord connectivity mapping. We do this using high field MRI. Our research aims at better understanding the central nervous system anatomical and functional connectivity. We are especially interested in looking at this in the context of neurological and neurodegenerative diseases.

Fun Fact

Members of our team have their roots in 7 countries (US, Turkey, France, India, Mauritius, South Korea, Ghana) and 4 continents (North America, Europe, Asia, Africa)

For More Information, check out the Center for Magnetic Resonance Research (CMRR) Website!


Written by Dr. Gulin Oz, Dr. Pierre-Gilles Henry, and Dr. Christophe Lenglet, Edited by Celeste Suart