English Archives -

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?

SCA1

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.

Newly identified mutations in SCA19/22 and their dysfunctions

Written by Sophia Leung Edited by Dr. Marija Cvetanovic

While the mutant proteins in SCA19/22 lose part of their innate functions and properties, they also disrupt the key functions of the normal healthy protein.

The underlying mechanism of the hereditary property of SCA19/22 is elusive. In this study, the researchers investigated the molecular properties of four different mutations found in patients with SCA19/22. They looked at how these mutant proteins affect the normal protein if they are both present in the cell. They found that the mutant proteins are not only non-functional (do not work properly), but that in their presence, the normal protein’s function is also diminished. Furthermore, while the production and proper localization of these mutant proteins are found to be defective, they also bring the same decline to the normal protein. This adds to their disease-causing properties. This study is significant in that it offers a molecular investigation into mutant proteins associated with SCA19/22 that was previously lacking. It also provides evidence that may explain the hereditary property of the disease.

A number of mutations in the gene KCND3 has been associated with SCA19/22. The gene makes the voltage‐gated potassium ion (K+) channel subunit KV4.3. In general terms, the gene makes a protein that functions to allow potassium ions to pass through the membrane of nerve cells. Similar to how a flute has many holes to allow air to pass through when played to make a specific note, a nerve cell has different kinds of channels to allow ions to pass through their membrane to orchestrate normal functioning. One could imagine the disruption to any channels, a partial obstruction or a total blockage, could perturb the overall output of the cell.

flute resting on a music stand — Similar to how a flute has many holes to allow air to pass through when played to make a specific note, a nerve cell has different kinds of channels to allow ions to pass through to orchestrate normal functioning. (Photo by Rajesh Kavasseri / Unsplash)

In this study, the researchers found that the normal K_V4.3 channel protein detectably allows potassium ions to pass through. But little to no ions can pass through the SCA19/22 mutant K_V4.3 channels. Even under the assistance of a “helper” protein, which normally enhances the function of this channel, only one of the mutant channel proteins shows improvement. This indicates that the SCA19/22 causing mutations result in a reduced function of mutated K_V4.3 channels.

Snapshot: What is Cerebrospinal Fluid (CSF)?

Public transit may not be the first thing that comes to mind when we think about the brain, but it’s a great way to understand how all the parts of the central nervous system work together. Nutrients, hormones, and other important molecules (the passengers) need to get on and off at different stations to do their work. They might first stop at the large internal chambers within the brain, called ventricles. From the ventricles, they can get to the central canal in the spinal cord, as well as the subarachnoid space. The subarachnoid space is a space between two membranes that surround the brain and spinal cord. It provides a stable structure for a network of veins and arteries.

The passengers are shuttled from station to station by the cerebrospinal fluid (CSF), a clear, colourless fluid that provides the central nervous system with necessary nutrients and hormones while carrying away waste products. CSF also cushions the brain and spinal cord by circulating between layers of tissues surrounding them. The whole public transit system is enclosed: the subarachnoid space and the ventricles are connected to the central canal in the spinal cord, forming a single reservoir for CSF.

Cerebrospinal fluid written in colorful letters under a Stethoscope on wooden background — Photo used under license by Sohel Parvez Haque/Shutterstock.com.

CSF is made by the choroid plexus, a collection of tiny blood vessels called capillaries. Capillaries filter the blood and secrete it into the ventricles. When the pressure of CSF is less than the pressure in the capillaries, CSF flows out and into the ventricles. When the pressure of CSF is greater than that of the bloodstream, the extra fluid is absorbed from the subarachnoid space and into sinuses (large areas filled with blood), where it can flow into the surrounding veins. The blood supply in the central nervous system tightly regulates the movement of molecules or cells between the blood and brain. This blood-brain barrier is crucial for protecting the brain from toxins and pathogens. Dysfunction of this specific system contributes to the development of neurological diseases.

Anatomical labeled scheme with human head and inside of skull, including superior sigittal sinus, ventricles, arachnoid Villi and spinal cord central canal. — Structure of the ventricles and central canal components that contribute to the public transit system. Photo used under license by VectorMine/Shutterstock.com.

Why is CSF Important for Neurodegenerative Diseases?

In neurodegenerative diseases like Spinocerebellar Ataxias, CSF contains molecules that can be used as biomarkers. Biomarkers are disease-specific proteins that change in concentration depending on disease stages. Biomarkers provide information on disease progression, with or without the impact of therapeutics. They are also crucial for understanding how disease processes work and assist in developing treatments.

The development of intrathecal injections, injecting into the central canal for distribution to the central nervous system (for example, spinal anesthesia), has been monumental for administering drugs in neurodegenerative diseases. In other words, not only can the public transit system of the central nervous system be investigated to see what passengers are associated with the disease, but it can be used to deliver “medicine passengers” to the place where the disease occurs.

If you would like to learn more about Cerebrospinal Fluid, take a look at these resources by MedlinePlus and WebMD.

Snapshot written by Kaitlyn Neuman and edited by Dr. Tamara Maiuri.